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Blood, 15 January 2006, Vol. 107, No. 2, pp. 415-416.
Platelet-collagen interaction: a new modulatorUNIVERSITY OF BRISTOL
C1q-TNF–related protein-1 (CTRP-1) is a new endogenous vascular cell wall regulator of collagen-induced platelet activation.
C1q-TNF superfamily members are variously insoluble structural proteins or freely soluble proteins found in serum and other fluid compartments of the body. CTRP-1 is produced predominantly by vascular smooth muscle cells, but also by endothelial cells, and its modular structure comprises a C-terminal globular C1q domain attached to a collagen-like region, which is typical of this family and is illustrated in the figure. In this issue of Blood, Lasser et al provide compelling evidence to show that soluble CTRP-1 binds fibrillar collagen type I, inhibiting collagen-induced platelet activation. There appear to be 2 sites of interaction within collagen for CTRP-1: a high-affinity and much more abundant site completely distinct from the classic GPP repeat recognition site for GPVI and a lower affinity site that overlaps with the GPVI binding motif. But the major mechanism by which CTRP-1 blocks collagen-dependent platelet function is through disruption of the interaction between VWF and collagen. In particular, VWF A3 domain has been shown to be the major interacting site with collagen, and CTRP-1 is shown here to compete with collagen for binding to VWF A3 domain.
The work presented has 2 important implications. First, CTRP-1 may represent an important novel endogenous mechanism regulating platelet responsiveness to exposed subendothelial surfaces. This requires much additional work but opens up a new field for study of endogenous negative regulatory processes. Second, because of the soluble nature of the protein, it has potential as a new therapeutic for control of arterial thrombosis. It will now be important to dissect further the interaction motifs in CTRP-1 for collagen and VWF, and in collagen for CTRP-1. I have speculated in the figure that the globular C1q domain may interact with collagen, whereas the collagen domain of CTRP-1 may interact with VWF A3 domain. The evidence for this is lacking at present, and is not investigated by Lasser et al in this study. The multiple inhibitory functions of CTRP-1 also make it difficult at this stage to assess which of its protein-protein interactions is pre-eminent in its antithrombotic role and in its ability to block collagen-induced platelet activation. In summary though, the identification of CTRP-1 as an endogenous and exogenous inhibitor of platelet responsiveness to collagen in vitro and in vivo opens up important new possibilities for both basic and applied platelet cell biology. References
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| Copyright © 2006 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
2
1 is not illustrated here. CTRP-1 blocks the activation of platelets by collagen through multiple mechanisms. CTRP-1 binds directly to abundant high-affinity, but uncharacterized, regions of collagen (depicted as blue rectangles) but also binds with lower affinity to sites that overlap with GPVI binding sites in collagen (depicted as tan rectangles). This disruption of GPVI-collagen interaction may partially explain the inhibitory action of CTRP-1. In addition, however, CTRP-1 disrupts VWF binding to collagen, by binding to the VWF A3 domain responsible for the collagen interaction. CTRP-1, therefore, interferes with collagen-induced platelet activation through several protein-protein interactions. The structure of CTRP-1 monomer is shown in the inset.