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

• DOI: 10.1038/s41467-019-10966-8
• Publication Date: 2019-07-17T10:02:58Z
• Authors: 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. More...; Evdoxia Karali; Naomi E. Chayen; Edward W. Tate; Mollie Jurewicz; Lawrence J. Stern; Chiara Recchi; Hani Gabra
• Keywords: EXPRESSION; BIOMARKER; 0301 basic medicine; Glycosylation; PROMOTER; Science; Mutation, Missense; 610; PROTEIN; NEURITE OUTGROWTH; Crystallography, X-Ray; GPI-Linked Proteins; Protein Aggregation, Pathological; OVARIAN-CANCER; Article; Epigenesis, Genetic; 03 medical and health sciences; Ovarian cancer; Structural Biology; Neoplasms; DIGLONS; MD Multidisciplinary; Humans; Neoplasm Invasiveness; Tumour-suppressor proteins; X-ray crystallography; Cancer Biology; Ovarian Neoplasms; 0303 health sciences; Science & Technology; Q; METHYLATION; Growth factor signalling; GENE; Cell invasion; Protein Structure, Tertiary; 3. Good health; Multidisciplinary Sciences; INTERFACE; Cell Transformation, Neoplastic; Science & Technology - Other Topics; Female; Cell Adhesion Molecules

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