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A Novel Talin-to-RhoA Switch Mechanism Upon Ligand Binding of the Collagen VI Receptor CMG2

49 Pages Posted: 11 Jun 2018 Publication Status: Review Complete

See all articles by Jérôme Bürgi

Jérôme Bürgi

Ecole Polytechnique Fédérale de Lausanne - Global Health Insitute

Laurence Abrami

Ecole Polytechnique Fédérale de Lausanne - Global Health Insitute

Irinka Castanon

University of Geneva - Department of Biochemistry

Shixu E. Yan

Ecole Polytechnique Fédérale de Lausanne - Global Health Insitute

Luciano A. Abriata

Ecole Polytechnique Fédérale de Lausanne - Institute of Bioengineering

Manuel Lera

University of Geneva - Department of Biochemistry

Sheila Unger

University of Lausanne - Division of Genetic Medicine

Andrea Superti-Furga

University of Lausanne - Division of Genetic Medicine

Matteo Dal Peraro

Ecole Polytechnique Fédérale de Lausanne - Institute of Bioengineering

Marcos Gonzalez Gaitan

University of Geneva - Department of Biochemistry

Gisou van der Goot

Ecole Polytechnique Fédérale de Lausanne - Global Health Insitute

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Abstract

The physiological role of Capillary Morphogenesis Gene 2 (CMG2), a receptor for both collagen VI and anthrax toxin, is poorly understood. Biallelic loss-of-function mutations produces the severe condition, Hyaline Fibromatosis Syndrome (HFS). We here report a novel mechanistic role for an extracellular matrix receptor. In contrast to integrins, CMG2 binds talin, and thereby the actin cytoskeleton, only in its ligand-free state. Upon extracellular ligand binding, CMG2 releases talin and accepts the binding of RhoA, an actin cytoskeleton regulator, and its effectors. We establish that HFS-associated mutations in the CMG2 cytosolic tail prevent talin binding, resulting in constitutive RhoA binding. Based on molecular dynamics simulations, we identify CMG2 residues responsible for talin or RhoA binding and demonstrated that effective switching between talin and RhoA binding is required for the intracellular degradation of collagen VI in mammalian cells as well as for the control of oriented cell division in fish development.

Suggested Citation

Bürgi, Jérôme and Abrami, Laurence and Castanon, Irinka and Yan, Shixu E. and Abriata, Luciano A. and Lera, Manuel and Unger, Sheila and Superti-Furga, Andrea and Peraro, Matteo Dal and Gonzalez Gaitan, Marcos and van der Goot, Gisou, A Novel Talin-to-RhoA Switch Mechanism Upon Ligand Binding of the Collagen VI Receptor CMG2 (2018). Available at SSRN: https://ssrn.com/abstract=3193408 or http://dx.doi.org/10.2139/ssrn.3193408
This version of the paper has not been formally peer reviewed.

Jérôme Bürgi

Ecole Polytechnique Fédérale de Lausanne - Global Health Insitute

1015 Lausanne
Switzerland

Laurence Abrami

Ecole Polytechnique Fédérale de Lausanne - Global Health Insitute

1015 Lausanne
Switzerland

Irinka Castanon

University of Geneva - Department of Biochemistry

1211 Geneva 4 – Suisse
Geneva
Switzerland

Shixu E. Yan

Ecole Polytechnique Fédérale de Lausanne - Global Health Insitute

1015 Lausanne
Switzerland

Luciano A. Abriata

Ecole Polytechnique Fédérale de Lausanne - Institute of Bioengineering

Station 5
Odyssea 1.04
1015 Lausanne, CH-1015
Switzerland

Manuel Lera

University of Geneva - Department of Biochemistry

1211 Geneva 4 – Suisse
Geneva
Switzerland

Sheila Unger

University of Lausanne - Division of Genetic Medicine

Station 5
Odyssea 1.04
1015 Lausanne, CH-1015
Switzerland

Andrea Superti-Furga

University of Lausanne - Division of Genetic Medicine

Station 5
Odyssea 1.04
1015 Lausanne, CH-1015
Switzerland

Matteo Dal Peraro

Ecole Polytechnique Fédérale de Lausanne - Institute of Bioengineering

Station 5
Odyssea 1.04
1015 Lausanne, CH-1015
Switzerland

Marcos Gonzalez Gaitan

University of Geneva - Department of Biochemistry

1211 Geneva 4 – Suisse
Geneva
Switzerland

Gisou Van der Goot (Contact Author)

Ecole Polytechnique Fédérale de Lausanne - Global Health Insitute ( email )

1015 Lausanne
Switzerland

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