Missense variant interaction scanning reveals a critical role of the FERM domain for tumor suppressor protein NF2 conformation and function

Author:

Moesslacher Christina S1,Auernig Elisabeth1ORCID,Woodsmith Jonathan1ORCID,Feichtner Andreas2ORCID,Jany-Luig Evelyne1,Jehle Stefanie3,Worseck Josephine M3,Heine Christian L1,Stefan Eduard245ORCID,Stelzl Ulrich1367ORCID

Affiliation:

1. Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, University of Graz

2. Institute of Biochemistry and Center for Molecular Biosciences, University of Innsbruck

3. Max-Planck Institute for Molecular Genetics (MPIMG), Otto-Warburg-Laboratory, Berlin, Germany

4. Tyrolean Cancer Research Institute (TKFI), Innsbruck, Austria

5. Institute of Molecular Biology, Innsbruck, Austria

6. BioTechMed-Graz, Graz, Austria

7. Field of Excellence BioHealth - University of Graz

Abstract

NF2 (moesin–ezrin–radixin-like [MERLIN] tumor suppressor) is frequently inactivated in cancer, where its NF2 tumor suppressor functionality is tightly coupled to protein conformation. How NF2 conformation is regulated and how NF2 conformation influences tumor suppressor activity is a largely open question. Here, we systematically characterized three NF2 conformation-dependent protein interactions utilizing deep mutational scanning interaction perturbation analyses. We identified two regions in NF2 with clustered mutations which affected conformation-dependent protein interactions. NF2 variants in the F2–F3 subdomain and the α3H helix region substantially modulated NF2 conformation and homomerization. Mutations in the F2–F3 subdomain altered proliferation in three cell lines and matched patterns of disease mutations in NF2 related-schwannomatosis. This study highlights the power of systematic mutational interaction perturbation analysis to identify missense variants impacting NF2 conformation and provides insight into NF2 tumor suppressor function.

Funder

Austrian Science Fund

Karl-Franzens-Universität Graz

Publisher

Life Science Alliance, LLC

Subject

Health, Toxicology and Mutagenesis,Plant Science,Biochemistry, Genetics and Molecular Biology (miscellaneous),Ecology

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