Multimerin 1 supports platelet function in vivo and binds to specific GPAGPOGPX motifs in fibrillar collagens that enhance platelet adhesion. (17th December 2020) - Leatherdale, Alexander
Abstract: Background: Multimerin 1 (human: MMRN1, mouse: Mmrn1) is a homopolymeric, adhesive, platelet and endothelial protein that binds to von Willebrand factor and enhances platelet adhesion to fibrillar collagen ex vivo. Objectives: To examine the impact of Mmrn1 deficiency on platelet adhesive function, and the molecular motifs in fibrillar collagen that bind MMRN1 to enhance platelet adhesion. Methods: Mmrn1‐deficient mice were generated and assessed for altered platelet adhesive function. Collagen Toolkit peptides, and other triple‐helical collagen peptides, were used to identify multimerin 1 binding motifs and their contribution to platelet adhesion. Results: MMRN1 bound to conserved GPAGPOGPX sequences in collagens I, II, and III (including GPAGPOGPI, GPAGPOGPV, and GPAGPOGPQ) that enhanced activated human platelet adhesion to collagen synergistically with other triple‐helical collagen peptides ( P < .05). Mmrn1 −/− and Mmrn1 +/− mice were viable and fertile, with complete and partial platelet Mmrn1 deficiency, respectively. Relative to wild‐type mice, Mmrn1 −/− and Mmrn1 +/− mice did not have overt bleeding, increased median bleeding times, or increased wound blood loss ( P ≥ .07); however, they both showed significantly impaired platelet adhesion and thrombus formation in the ferric chloride injury model ( P ≤ .0003). Mmrn1 −/− platelets had impaired adhesion to GPAGPOGPX peptides and fibrillar collagen ( P ≤ .03) and formed smaller aggregates than wild‐type platelets when captured onto collagen, triple‐helical collagen mimetic peptides, von Willebrand factor, or fibrinogen ( P ≤ .008), despite preserved, low shear, and high shear aggregation responses. Conclusions: Multimerin 1 supports platelet adhesion and thrombus formation and binds to highly conserved, GPAGPOGPX motifs in fibrillar collagens that synergistically enhance platelet adhesion.