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Science. 2018 Mar 2;359(6379):1042-1046. doi: 10.1126/science.aaq1739.

Accurate computational design of multipass transmembrane proteins.

Author information

1
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
2
Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
3
Department of Chemistry and Biochemistry, UCLA-DOE Institute, Molecular Biology Institute, University of California, Los Angeles (UCLA), CA 90095, USA.
4
Department of Bioengineering and Biophysics Group, University of California, Berkeley, Berkeley, CA 94720, USA.
5
Department of Biological Structure, University of Washington, Seattle, WA 98195, USA.
6
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. dabaker@u.washington.edu.
7
Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.

Abstract

The computational design of transmembrane proteins with more than one membrane-spanning region remains a major challenge. We report the design of transmembrane monomers, homodimers, trimers, and tetramers with 76 to 215 residue subunits containing two to four membrane-spanning regions and up to 860 total residues that adopt the target oligomerization state in detergent solution. The designed proteins localize to the plasma membrane in bacteria and in mammalian cells, and magnetic tweezer unfolding experiments in the membrane indicate that they are very stable. Crystal structures of the designed dimer and tetramer-a rocket-shaped structure with a wide cytoplasmic base that funnels into eight transmembrane helices-are very close to the design models. Our results pave the way for the design of multispan membrane proteins with new functions.

PMID:
29496880
DOI:
10.1126/science.aaq1739
[Indexed for MEDLINE]

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