Characterization of a novel RP2-OSTF1 interaction and its implication for actin remodeling

Author:

Lyraki Rodanthi1,Lokaj Mandy2,Soares Dinesh C.1ORCID,Little Abigail1,Vermeren Matthieu13ORCID,Marsh Joseph A.1ORCID,Wittinghofer Alfred2ORCID,Hurd Toby1ORCID

Affiliation:

1. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, EH4 2XU, UK

2. Structural Biology Group, Max-Planck Institut für Molekulare Physiologie, Abteilung Strukturelle Biologie, Otto-Hahn-Str. 11, 44227, Dortmund, Germany

3. MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, EH16 4TJ, UK

Abstract

Retinitis pigmentosa 2 (RP2) is the causative gene for a form of X-linked retinal degeneration. RP2 was previously shown to have GAP activity towards the small GTPase ARL3 via its N-terminus, but the function of the C-terminus remains elusive. Here, we report a novel interaction between RP2 and Osteoclast-stimulating factor 1 (OSTF1), an intracellular protein that indirectly enhances osteoclast formation and activity and is a negative regulator of cell motility. Moreover, this interaction is abolished by a human pathogenic mutation in RP2. We utilized a structure-based approach to pinpoint the binding interface to a strictly conserved cluster of residues on the surface of RP2 that spans both the C- and N- terminal domains of the protein, and which is structurally distinct from the ARL3 binding site. In addition, we show that RP2 is a positive regulator of cell motility in vitro, recruiting OSTF1 to the cell membrane and preventing its interaction with the migration regulator Myo1E.

Funder

Retinitis Pigmentosa Fighting Blindness

European Research Council

Medical Research Council

Publisher

The Company of Biologists

Subject

Cell Biology

Reference55 articles.

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