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Science. 2019 Mar 29;363(6434):1418-1423. doi: 10.1126/science.aav7541.

Packing of apolar side chains enables accurate design of highly stable membrane proteins.

Author information

1
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
2
State Key Laboratory of Chemical Oncogenomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China. lijunliuks@gmail.com william.degrado@ucsf.edu.
3
DLX Scientific, Lawrence, KS 66049, USA.
4
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA. lijunliuks@gmail.com william.degrado@ucsf.edu.

Abstract

The features that stabilize the structures of membrane proteins remain poorly understood. Polar interactions contribute modestly, and the hydrophobic effect contributes little to the energetics of apolar side-chain packing in membranes. Disruption of steric packing can destabilize the native folds of membrane proteins, but is packing alone sufficient to drive folding in lipids? If so, then membrane proteins stabilized by this feature should be readily designed and structurally characterized-yet this has not been achieved. Through simulation of the natural protein phospholamban and redesign of variants, we define a steric packing code underlying its assembly. Synthetic membrane proteins designed using this code and stabilized entirely by apolar side chains conform to the intended fold. Although highly stable, the steric complementarity required for their folding is surprisingly stringent. Structural informatics shows that the designed packing motif recurs across the proteome, emphasizing a prominent role for precise apolar packing in membrane protein folding, stabilization, and evolution.

PMID:
30923216
DOI:
10.1126/science.aav7541
[Indexed for MEDLINE]

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