Structural Basis for MCAM Mediated Inhibition of Laminin Dependent Cell Migration
- 1Yale University
Abstract
MCAM/CD146 is an immunoglobulin-superfamily receptor expressed on endothelial cells, immune cells and numerous carcinomas. Although MCAM has long been associated with metastatic progression, recent work has revealed context-dependent inhibitory effects on transendothelial migration, leaving unresolved how MCAM engagement of basement membrane laminins alters cell migration. Here, we report multiple cryo-electron microscopy structures of human MCAM bound to laminin. We show MCAM engages laminin on a surface centered on the first two laminin globular domains (LG1-2) and that this epitope directly overlaps with the interface used by integrin. Consistent with structural competition, MCAM occupation of laminin abolishes integrin-dependent cell migration. Structure-guided mutation of the MCAM-laminin interface disrupts laminin binding and eliminates MCAM-mediated inhibition. These findings establish that MCAM and integrin compete for a shared interface on laminin and define a structural mechanism by which MCAM occupancy can suppress laminin-dependent migration. The structure resolves a central ambiguity in MCAM biology and provides a framework for developing biologics that selectively modulate pathological cell migration.
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BibTeX
@misc{klein2026structural,
title = {{Structural Basis for MCAM Mediated Inhibition of Laminin Dependent Cell Migration}},
author = {D. E. Klein and T. Li and S. Alarcon-Frias and H. Li and C. Alarcon},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.11.751044},
url = {https://www.biorxiv.org/content/10.64898/2026.09.11.751044v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Structural Basis for MCAM Mediated Inhibition of Laminin Dependent Cell Migration
AU - D. E. Klein
AU - T. Li
AU - S. Alarcon-Frias
AU - H. Li
AU - C. Alarcon
PY - 2026
DA - 2026/09/11
PB - bioRxiv
DO - 10.64898/2026.09.11.751044
UR - https://www.biorxiv.org/content/10.64898/2026.09.11.751044v1
AB - MCAM/CD146 is an immunoglobulin-superfamily receptor expressed on endothelial cells, immune cells and numerous carcinomas. Although MCAM has long been associated with metastatic progression, recent work has revealed context-dependent inhibitory effects on transendothelial migration, leaving unresolved how MCAM engagement of basement membrane laminins alters cell migration. Here, we report multiple cryo-electron microscopy structures of human MCAM bound to laminin. We show MCAM engages laminin on a surface centered on the first two laminin globular domains (LG1-2) and that this epitope directly overlaps with the interface used by integrin. Consistent with structural competition, MCAM occupation of laminin abolishes integrin-dependent cell migration. Structure-guided mutation of the MCAM-laminin interface disrupts laminin binding and eliminates MCAM-mediated inhibition. These findings establish that MCAM and integrin compete for a shared interface on laminin and define a structural mechanism by which MCAM occupancy can suppress laminin-dependent migration. The structure resolves a central ambiguity in MCAM biology and provides a framework for developing biologics that selectively modulate pathological cell migration.
ER -