Inactivating mutations and X-ray crystal structure of the tumor suppressor OPCML reveal cancer-associated functions

James R. Birtley, Mohammad Alomary, Elisa Zanini, Jane Antony, Zachary Maben, Grant C. Weaver, Claudia Von Arx, Manuela Mura, Aline T. Marinho, Haonan Lu, Eloise V. N. Morecroft, Evdoxia Karali, Naomi E. Chayen, Edward W. Tate, Mollie Jurewicz, Lawrence J. Stern (), Chiara Recchi () and Hani Gabra ()
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James R. Birtley: University of Massachusetts Medical School
Mohammad Alomary: Imperial College London
Elisa Zanini: Imperial College London
Jane Antony: Imperial College London
Zachary Maben: University of Massachusetts Medical School
Grant C. Weaver: University of Massachusetts Medical School
Claudia Von Arx: Imperial College London
Manuela Mura: Imperial College London
Aline T. Marinho: Imperial College London
Haonan Lu: Imperial College London
Eloise V. N. Morecroft: Imperial College London
Evdoxia Karali: Imperial College London
Naomi E. Chayen: Imperial College London
Edward W. Tate: Imperial College London
Mollie Jurewicz: University of Massachusetts Medical School
Lawrence J. Stern: University of Massachusetts Medical School
Chiara Recchi: Imperial College London
Hani Gabra: Imperial College London

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract OPCML, a tumor suppressor gene, is frequently silenced epigenetically in ovarian and other cancers. Here we report, by analysis of databases of tumor sequences, the observation of OPCML somatic missense mutations from various tumor types and the impact of these mutations on OPCML function, by solving the X-ray crystal structure of this glycoprotein to 2.65 Å resolution. OPCML consists of an extended arrangement of three immunoglobulin-like domains and homodimerizes via a network of contacts between membrane-distal domains. We report the generation of a panel of OPCML variants with representative clinical mutations and demonstrate clear phenotypic effects in vitro and in vivo including changes to anchorage-independent growth, interaction with activated cognate receptor tyrosine kinases, cellular migration, invasion in vitro and tumor growth in vivo. Our results suggest that clinically occurring somatic missense mutations in OPCML have the potential to contribute to tumorigenesis in a variety of cancers.

Date: 2019
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DOI: 10.1038/s41467-019-10966-8

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