The Cysteine-rich Domain of Snake Venom Metalloproteinases Is a Ligand for von Willebrand Factor A Domains

Snake venom metalloproteinases (SVMPs) are members of the Reprolysin family of metalloproteinases to which the ADAM (a disintegrin and metalloproteinase) proteins also belong. The disintegrin-like/cysteine-rich domains of the ADAMs have been implicated in their function. In the case of the SVMPs, we hypothesized that these domains could function to target the metalloproteinases to key extracellular matrix proteins or cell surface proteins. Initially we detected interaction of collagen XIV, a fibril-associated collagen with interrupted triple helices containing von Willebrand factor A (VWA) domains, with the PIII SVMP catrocollastatin. Next we investigated whether other VWA domain-containing matrix proteins could support the binding of PIII SVMPs. Using surface plasmon resonance, the PIII SVMP jararhagin and a recombinant cysteine-rich domain from a PIII SVMP were demonstrated to bind to collagen XIV, collagen XII, and matrilins 1, 3, and 4. Jararhagin was shown to cleave these proteins predominantly at sites localized at or near the VWA domains suggesting that it is the VWA domains to which the PIII SVMPs are binding via their cysteine-rich domain. In light of the fact that these extracellular matrix proteins function to stabilize matrix, targeting the SVMPs to these proteins followed by their specific cleavage could promote the destabilization of extracellular matrix and cell-matrix interactions and in the case of capillaries could contribute to their disruption and hemorrhage. Although there is only limited structural homology shared by the cysteine-rich domains of the PIII SVMPs and the ADAMs our results suggest an analogous function for the cysteine-rich domains in certain members of the expanded ADAM family of proteins to target them to VWA domain-containing proteins. Snake venom metalloproteinases (SVMPs) are members of the Reprolysin family of metalloproteinases to which the ADAM (a disintegrin and metalloproteinase) proteins also belong. The disintegrin-like/cysteine-rich domains of the ADAMs have been implicated in their function. In the case of the SVMPs, we hypothesized that these domains could function to target the metalloproteinases to key extracellular matrix proteins or cell surface proteins. Initially we detected interaction of collagen XIV, a fibril-associated collagen with interrupted triple helices containing von Willebrand factor A (VWA) domains, with the PIII SVMP catrocollastatin. Next we investigated whether other VWA domain-containing matrix proteins could support the binding of PIII SVMPs. Using surface plasmon resonance, the PIII SVMP jararhagin and a recombinant cysteine-rich domain from a PIII SVMP were demonstrated to bind to collagen XIV, collagen XII, and matrilins 1, 3, and 4. Jararhagin was shown to cleave these proteins predominantly at sites localized at or near the VWA domains suggesting that it is the VWA domains to which the PIII SVMPs are binding via their cysteine-rich domain. In light of the fact that these extracellular matrix proteins function to stabilize matrix, targeting the SVMPs to these proteins followed by their specific cleavage could promote the destabilization of extracellular matrix and cell-matrix interactions and in the case of capillaries could contribute to their disruption and hemorrhage. Although there is only limited structural homology shared by the cysteine-rich domains of the PIII SVMPs and the ADAMs our results suggest an analogous function for the cysteine-rich domains in certain members of the expanded ADAM family of proteins to target them to VWA domain-containing proteins. One of the hallmarks of viperid envenoming is local hemorrhage caused by the snake venom metalloproteinases (SVMPs) 2The abbreviations used are: SVMP, snake venom metalloproteinase; VWA, von Willebrand factor A; ADAM, a disintegrin and metalloproteinase; ADAMTS, a disintegrin and metalloproteinase with thrombospondin type 1 motifs; FACIT, fibril-associated collagen with interrupted triple helices; EGF, epidermal growth factor; PBS, phosphate-buffered saline. (1Ownby C.L. Bjarnason J. Tu A.T. Am. J. Pathol. 1978; 93: 201-218PubMed Google Scholar, 2Ohsaka A. Ikezawa H. Kondo H. Kondo S. Uchida N. Br. J. Exp. Pathol. 1960; 41: 478-486PubMed Google Scholar). SVMPs are members of the Reprolysin subfamily of the M12 family of metalloproteinases (3Bjarnason J.B. Fox J.W. Methods Enzymol. 1995; 248: 345-368Crossref PubMed Scopus (245) Google Scholar). Of the SVMPs, the PIII class is distinguished by being comprised of proproteinase, proteinase, disintegrin-like, and cysteine-rich domains (4Fox J.W. Serrano S.M.T. Toxicon. 2005; 45: 969-985Crossref PubMed Scopus (429) Google Scholar). The proteinase domain of all the SVMP hemorrhagic toxins is believed to function to degrade capillary basement membranes, endothelial cell surfaces, and stromal matrix ultimately causing extravasation of capillary contents into the surround stroma (5Baramova E.N. Shannon J.D. Bjarnason J.B. Fox J.W. Arch. Biochem. Biophys. 1989; 275: 63-71Crossref PubMed Scopus (202) Google Scholar, 6Shannon J.D. Baramova E.N. Bjarnason J.B. Fox J.W. J. Biol. Chem. 1989; 264: 11575-11583Abstract Full Text PDF PubMed Google Scholar). Interestingly the PIII class of SVMPs is typically much more potent in causing hemorrhage compared with the PI and PII classes that lack the cysteine-rich domain found in the PIII class (4Fox J.W. Serrano S.M.T. Toxicon. 2005; 45: 969-985Crossref PubMed Scopus (429) Google Scholar) suggesting a role for this domain in the pathophysiology of the PIII hemorrhagic toxins. Indeed the disintegrin-like/cysteine-rich domains of certain hemorrhagic toxins have been shown to be potent inhibitors of collagen-induced platelet aggregation as a result of interaction of the cysteine-rich domain with the α2β1 integrin on platelets (7Jia L.G. Wang X.M. Shannon J.D. Bjarnason J.B. Fox J.W. Arch. Biochem. Biophys. 2000; 373: 281-286Crossref PubMed Scopus (69) Google Scholar, 8Zigrino P. Kamiguti A.S. Eble J. Drescher C. Nischt R. Fox J.W. Mauch C. J. Biol. Chem. 2002; 277: 40528-40535Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). Proteolytic degradation of capillary basement membrane structures and inhibition of platelet aggregation have been considered to be the key features underlying the hemorrhagic potency of PIII SVMP hemorrhagic toxins (5Baramova E.N. Shannon J.D. Bjarnason J.B. Fox J.W. Arch. Biochem. Biophys. 1989; 275: 63-71Crossref PubMed Scopus (202) Google Scholar, 9Kamiguti A.S. Hay C.R. Theakston R.D. Zuzel M. Toxicon. 1996; 34: 627-642Crossref PubMed Scopus (186) Google Scholar). Similarly recent studies from our laboratory demonstrated the ability of natural disintegrin-like/cysteine-rich domains processed from PIII SVMPs, as well as a recombinant cysteine-rich domain based on the structure from the PIII SVMP atrolysin A proteinase from Crotalus atrox venom, to support the interaction of the PIII SVMPs with von Willebrand factor (10Serrano S.M.T. Jia L.G. Wang D. Shannon J.D. Fox J.W. Biochem. J. 2005; 391: 69-76Crossref PubMed Scopus (59) Google Scholar). Thus, these studies indicate that the non-proteinase domains, particularly the cysteine-rich domain, of the PIII SVMPs play an important role in the pathophysiology of the toxins targeting the proteinase domain to relevant substrates to promote hemorrhage. This leads to the question of whether there are conserved structural motifs in other relevant proteins that can support PIII SVMP binding and thus targeting proteolysis by the SVMPs. von Willebrand factor (VWF), a plasma and extracellular matrix protein, contains three von Willebrand factor A domains (referred to as VWA1, VWA2, and VWA3). VWA domains are involved in cell adhesion and are present in extracellular matrix proteins and in integrin receptors (11Whittaker C.A. Hynes R.O. Mol. Biol. Cell. 2002; 13: 3369-3387Crossref PubMed Scopus (537) Google Scholar). Among the VWA-containing proteins are the fibril-associated collagens with interrupted triple helices (FACITs) that form a subclass of collagens characterized by the presence of more than one triple helical domain separated by non-triple helical segments. collagens S. A. PubMed Scopus Google Scholar) and P. M. R. J. Biochem. PubMed Scopus Google Scholar, J.W. P. M. R. M. J. Biol. Chem. Full Text PDF PubMed Google Scholar) have one domain that the to the surface of the and three domains containing 1995; PubMed Scopus Google Scholar). Among the VWA-containing extracellular matrix proteins are the 1, and VWA domains that a of domains, in the VWA domain is are to play a role in the of or structures with collagens R. M. 2005; PubMed Scopus Google Scholar). the structural features of PIII SVMPs and their ability to target substrates as well as to into the of hemorrhage by these toxins we in studies to the of venom proteins with cell and cell proteins. on our studies we that an extracellular protein, collagen XIV, was as a binding of a PIII SVMP, from C. atrox The ability of PIII SVMPs to with collagen was PIII SVMP, from venom with surface plasmon This interaction was to XII, as well as the extracellular matrix proteins 1, 3, and all proteins containing VWA also demonstrated that interaction of the PIII SVMPs with these proteins was via the cysteine-rich domain that to target SVMP proteolysis to at or near their VWA in these proteins. In we have binding for PIII SVMPs that the cysteine-rich domain to binding to VWA domains and target them for A role for collagen and and 1, 3, and degradation in hemorrhage is their presence in the stroma capillaries in and their role in matrix one can on their to capillary and thus their degradation by the hemorrhagic SVMPs contribute to hemorrhage via capillary domain from atrolysin was as (10Serrano S.M.T. Jia L.G. Wang D. Shannon J.D. Fox J.W. Biochem. J. 2005; 391: 69-76Crossref PubMed Scopus (59) Google a PIII hemorrhagic SVMP from venom Theakston R.D. J. Biol. Chem. Full Text PDF PubMed Google was a from M. collagen and collagen were as J. Biol. Chem. Full Text PDF PubMed Google Scholar). as from the This the and with the VWA domain. 1 was from as S. J. M. R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google recombinant matrilins 3, and S. J. M. R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) and VWA domains and were as S. J. M. R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The the VWA domain was a from and was by that an at the and a at the and with and the was into the with a with the of P. C. R. PubMed Scopus Google Scholar). The the domains was by that an at the and a at the and and into the with a with the of P. C. R. PubMed Scopus Google Scholar). for the type domains of collagen was by that a at the and a at the and The was into a a and a cleavage with the recombinant were with 1 and for at The were and in containing The were followed by of cell by a with the was to a and with a containing of by cleavage was at 1 and the was by the to a to in were from by a in phosphate-buffered and The cell was in 1 and with a for at The was at for at and the was The was and The was with the other and at for The was in and at for The cell was with in and 1 at for the was at for 1 at and the membrane proteins were in the of of the cell membrane was with of in for on The was by and the proteins were separated from the by a of C. atrox of C. atrox venom was with of in for on the was for at and at of and of venom proteins in was with of the cell membrane for at with stabilize proteins the was with 1 for in The was for at followed by of to a of and to a of This was with for at with followed by with binding followed by with binding containing The proteins were on a PubMed Scopus Google Scholar) followed by of a a with a in the were and with J.B. 2000; Scopus Google Scholar). were by with a with a to a capillary of of were and the were from the by an at a of The was at The was the play of the to and to in The were by the interactions were by surface plasmon with a or collagen was on the to the of the the was with a of and for or collagen in was an for at a of at on the matrix were with 1 at of collagen and collagen on in surface of and of jararhagin and were in and at a of matrilins 1, 3, and or VWA domains and were by the in for at a of at in surface of and of the recombinant were in and at a of type domains in or domains in were by the for at a of at in surface of and A of jararhagin was in and at a of The of and to a was used for the of were a of of collagen or was with of jararhagin for and at in as were of collagen and jararhagin were by of and to on the were with were with a and were from the One sites of of collagen was with of jararhagin as and proteins were to membrane and with the was in a and proteins were at A for at a of to membrane at the membrane with the membrane was a and of were for the membrane with the were in an the The of the collagens were localized by based on their the of the from and the of these proteins the The is of a of three were from to M. D. M. J. PubMed Scopus Google Scholar) and in with with and were to for followed by of jararhagin to a of or and for or at The was with and 1 at to cell and used for of collagen P. R. M. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) was to the lack of of 1 and the lack of binding of to proteolysis were with only matrilins and 4. In these of or of was with and of for at in as were of matrilins and jararhagin were by at on that were with were with a and were One in the case of the the of the proteolysis were based on their their from and their The is of a of three of C. atrox this was to to venom shown in 1, the was to venom proteins with and cell proteins with the of the interactions were by The on these proteins were that the was a only proteins and with venom be of the and via of be of containing cell and venom proteins were to and the with the in 1 from the C. atrox PIII SVMP, and the collagen of the PIII SVMP Jararhagin and the from the PIII SVMP A with and with these studies was to the interaction of class PIII SVMPs with the collagens and to the interaction domain on the PIII SVMPs. this a PIII SVMP from venom, and a recombinant cysteine-rich domain of atrolysin A from C. atrox venom were to their ability to bind to collagens and XIV, containing VWA domains, surface plasmon in 1, jararhagin 1, A and and the recombinant cysteine-rich domain 1, and were of with collagens and XIV, in a The of these interactions are shown in Interestingly the recombinant PIII cysteine-rich domain demonstrated interaction to collagens and than the SVMP In interaction surface plasmon jararhagin binding to recombinant collagen type domains that the interactions with collagens are by the VWA domains present in collagens and of the interaction of jararhagin and cysteine-rich domain of PIII SVMP atrolysin with collagens and on in the on in a of the of A with the that other PIII SVMPs containing cysteine-rich domains could bind to VWA domain-containing matrix proteins we the ability of the recombinant C. atrox from atrolysin A to bind to matrilins in was of binding to matrilins 1, 3, and in a binding was and The of these interactions are shown in The binding of to matrilins 1, 3, and was all in the the interaction with matrilins 1 and was than with 4. binding was detected we the interaction of jararhagin with a recombinant to the domains of the interaction of with matrilins and VWA domains on in the on in a of the of A with and VWA the results of the interaction of with the recombinant domain and the and domains surface plasmon to the three VWA domains in the The binding to the VWA domains was with were than the for binding to the domain. the binding for with the matrilins in that for binding to matrilins 1 and were than that for 4. of and and and of extracellular matrix is considered to be a factor in the of hemorrhage by certain SVMPs, the ability of jararhagin to cleave collagens and and matrilins and was in A and collagens and XIV, limited proteolysis by jararhagin from the collagens with jararhagin to that the sites of cleavage in the collagens were localized to or to VWA domains and In the case of collagen in the domain to one with localized in the domain and with their localized at or to the domain and their localized to the of the collagen XIV, to the domain with localized to in or to the domain and One proteins with in the domain and to the domain with their localized to the collagen domain. proteins with to the domain with localized to the collagen domain and the domain in the of the type domain to the also proteins with to the of the domain with localized to the to the domain. our that PIII SVMPs as jararhagin with these collagens by of their cysteine-rich domain binding to VWA domains in the collagens and in promote proteolysis at sites on or the VWA sites of collagen XII, collagen XIV, and by of of cleavage of cleavage based on of of of the the of as domain type of of to the thrombospondin of type domain domain domain domain domain domain domain type domain type type type type of of of of of in a of jararhagin cleavage sites in collagens and and sites of domain of collagen by the was present in the collagen the of the of jararhagin on collagens in a matrix, jararhagin was also to cleave collagen in the extracellular matrix by the degradation detected by an of with jararhagin that collagen was in a and jararhagin was with matrilins and of proteolysis by jararhagin of jararhagin with of these and A three proteins with to the domain with localized to the of the and proteins with their the VWA domain and the at the of the was to proteins with their at the of the VWA domain and with their localized to the of the in the case with collagens and XIV, jararhagin cleavage of was at or to the VWA domain suggesting specific interaction with that domain. The proteolysis of by jararhagin is shown in there was of by the to one can that the cleavage at is the result of a of from the or that the cleavage or to the or domain, the there been suggesting the interaction of members of the Reprolysin family of metalloproteinases with proteins that von Willebrand factor A The PIII SVMP jararhagin been demonstrated to bind to and cleave and the integrin α2β1 A.S. Hay C.R. Theakston R.D. Zuzel M. Toxicon. 1996; 34: 627-642Crossref PubMed Scopus (186) Google Scholar). In binding to these proteins in cleavage of the the sites of and were of the Reprolysin been demonstrated to function in by binding to and it to the of the von Willebrand factor A. 2002; PubMed Scopus Google Scholar). the in the domain of to from the M. R. 1996; Scholar). In recent studies a of recombinant of VWA domains, the of interaction of on as well as been to the domain M. PubMed Scopus Google Scholar, S. A. PubMed Scopus Google Scholar, S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). have investigated the of that are involved in M. H. H. H. C. PubMed Scopus Google Scholar) demonstrated that the domains of are for proteolysis of Similarly and J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar) have shown that of the thrombospondin type 1 binding to the domain binding thus the cysteine-rich the domain as a role in studies with PIII SVMPs and have that the in these proteins involved in VWA domain interaction in the disintegrin-like/cysteine-rich domain. PIII SVMPs, jararhagin from venom, atrolysin A from C. atrox venom, and from venom, have been demonstrated to bind cleave A.S. Hay C.R. Theakston R.D. Zuzel M. Toxicon. 1996; 34: 627-642Crossref PubMed Scopus (186) Google Scholar, S.M.T. Jia L.G. Wang D. Shannon J.D. Fox J.W. Biochem. J. 2005; 391: 69-76Crossref PubMed Scopus (59) Google Scholar, J. S. S. M. PubMed Scopus (60) Google Scholar). In the case of the of cleavage in was at in the of the domain J. S. S. M. PubMed Scopus (60) Google Scholar). This cleavage of and that are of platelet aggregation J. S. S. M. PubMed Scopus (60) Google Scholar). for which of the PIII is involved in is compared with only the PIII SVMPs have been demonstrated to bind suggesting a role for their disintegrin-like/cysteine-rich The that the cysteine-rich domain of PIII SVMPs play a role was by Jia (7Jia L.G. Wang X.M. Shannon J.D. Bjarnason J.B. Fox J.W. Arch. Biochem. Biophys. 2000; 373: 281-286Crossref PubMed Scopus (69) Google Scholar, L.G. Wang X.M. Shannon J.D. Bjarnason J.B. Fox J.W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) that the recombinant disintegrin-like/cysteine-rich domain of the PIII SVMP atrolysin A as well as the recombinant cysteine-rich domain could platelet studies a interaction of the cysteine-rich domain with the platelet collagen which a VWA domain. P. Kamiguti A.S. Eble J. Drescher C. Nischt R. Fox J.W. Mauch C. J. Biol. Chem. 2002; 277: 40528-40535Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar) these results by that the PIII SVMP jararhagin to the α2β1 integrin in a Serrano (10Serrano S.M.T. Jia L.G. Wang D. Shannon J.D. Fox J.W. Biochem. J. 2005; 391: 69-76Crossref PubMed Scopus (59) Google Scholar) that the recombinant cysteine-rich domain of atrolysin A could bind to and interaction with an of a role for the cysteine-rich domain of PIII SVMPs. This was by the of Kamiguti A.S. P. C. Theakston Zuzel M. Fox J.W. PubMed Scopus Google Scholar) that from the cysteine-rich domain of atrolysin A and jararhagin could platelet aggregation and cell adhesion to Thus, there are that certain members of the Reprolysin as and the PIII SVMPs, could target proteins containing VWA domains and cleavage of the proteins. the of other surface interactions we a to venom surface we were to an interaction the PIII SVMP and collagen This interaction was localized to the cysteine-rich domain of a recombinant this domain of atrolysin A. is a of the a of collagens that function as in extracellular Biochem. Full Text PDF PubMed Scopus Google Scholar). is comprised of domain type domains, VWA domains, one thrombospondin domain, collagen domains, and domains Biol. PubMed Scopus Google Scholar). is to play a role in matrix by with collagen their domains D. 2002; PubMed Scopus Google Scholar). we have shown PIII SVMPs can bind to collagen via cysteine-rich domain and cleave the collagen at sites on or near the and domains suggesting that the binding on collagen for the cysteine-rich domain in the PIII SVMPs is the VWA whether the interaction of matrix proteins containing VWA domains with PIII SVMPs is a we the ability of three other proteins to support cysteine-rich PIII SVMP is also a collagen with VWA domains 1995; PubMed Scopus Google Scholar). Using the of collagen the VWA domains we demonstrated cysteine-rich binding to collagen with localized in the domain, PIII SVMP cysteine-rich domain interaction with VWA the interaction and cleavage of collagen by jararhagin was demonstrated to in matrix by to the of this extracellular matrix as a target for The fact that jararhagin was to bind to a comprised of the type domains of collagen XII, the VWA domains, the role of the VWA domain in the of collagen by family of extracellular matrix proteins that VWA domains is the matrilins R. M. 2005; PubMed Scopus Google Scholar). This family is comprised of members that are proteins predominantly in the collagens to other matrix proteins as collagens and 1, and VWA domains separated by only one VWA domain followed by The matrilins by their VWA Using matrilins we were to cysteine-rich domain binding with all recombinant and and domains we also demonstrated their ability to with PIII SVMP cysteine-rich domain. The lack of binding to could be by a of the binding to a of VWA domains as been shown by D. S. M. N. D. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). also whether the PIII SVMP jararhagin could cleave matrilins and and as was with collagens and cleavage was detected at or near the VWA domain in the case of that the interactions of the PIII SVMPs to the matrilins are by the VWA domain, binding was by surface plasmon jararhagin was a recombinant form of the VWA the structure of the PIII SVMP was S. H. S. J. PubMed Scopus Google Scholar). of the structure that the of the domain of the PIII was for the cysteine-rich domain was for This our that the cysteine-rich domain is of and for One can the disintegrin-like/cysteine-rich domains have been processed from the and the domain support based on the this is the case in the with the disintegrin-like/cysteine-rich domains in the of the metalloproteinase domain. Interestingly in recent it was shown that a PIII metalloproteinase from the venom of was to the of the by the interaction of with Mol. 2005; PubMed Scopus Google Scholar). factor contains a VWA one can that with VWA domain via cysteine-rich domain thus the binding of and that is to be on sites the VWA domain. of the of the of PIII SVMPs, and and cysteine-rich domains that structure is from that of the SVMPs and ADAMs in the domain and one in the cysteine-rich domain the of is also conserved in the and cysteine-rich domains compared with the SVMPs and the ADAMs it is that the structure of the disintegrin-like/cysteine-rich domains of is from that of the SVMPs or the one can that the motifs present in the cysteine-rich domains of the SVMPs and that play a role in VWA domain interaction are based on in a motifs in the cysteine-rich domains of SVMPs and and VWA domains can Thus, from the in this we can that the cysteine-rich domain of PIII SVMPs to target the proteinase to these extracellular matrix by binding to their VWA domains followed by cleavage at or near the VWA domain. In the case of interaction with PIII SVMPs and to in the case of the and a of in the the important role collagens and play in collagen structure and the function of matrilins as proteins matrix proteins it is to suggest that targeting and these proteins by the PIII SVMPs could play an important role in their the of local and hemorrhage A. Ikezawa H. Kondo H. Kondo S. Uchida N. Br. J. Exp. Pathol. 1960; 41: 478-486PubMed Google Scholar, J.B. Fox J.W. Methods Enzymol. 1995; 248: 345-368Crossref PubMed Scopus (245) Google Scholar). we have shown that the hemorrhagic SVMPs were potent of capillary basement membrane degradation that leads to in the capillary the of capillary contents into the stroma (5Baramova E.N. Shannon J.D. Bjarnason J.B. Fox J.W. Arch. Biochem. Biophys. 1989; 275: 63-71Crossref PubMed Scopus (202) Google Scholar, 6Shannon J.D. Baramova E.N. Bjarnason J.B. Fox J.W. J. Biol. Chem. 1989; 264: 11575-11583Abstract Full Text PDF PubMed Google Scholar). The basement the capillaries are in with and by the stromal matrix, and proteins involved in stromal matrix could promote or the destabilization of basement and contribute to the hemorrhagic to this are in our This to a of that toxins are of as by the PIII SVMPs and the the of the toxins are to their presence at the or or at an in the based on these one can that the presence of VWA domains in matrix as well as other of a function. The role of VWA domains as targeting sites for ADAM for of the with the result of function in with a be more than the of and and thus a of for with

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