NDLI: A minimal sequence code for switching protein structure and function

Content Provider	PubMed Central
Author	Alexander, Patrick A. He, Yanan Chen, Yihong Orban, John Bryan, Philip N.
Abstract	We present here a structural and mechanistic description of how a protein changes its fold and function, mutation by mutation. Our approach was to create 2 proteins that (i) are stably folded into 2 different folds, (ii) have 2 different functions, and (iii) are very similar in sequence. In this simplified sequence space we explore the mutational path from one fold to another. We show that an IgG-binding, 4β+α fold can be transformed into an albumin-binding, 3-α fold via a mutational pathway in which neither function nor native structure is completely lost. The stabilities of all mutants along the pathway are evaluated, key high-resolution structures are determined by NMR, and an explanation of the switching mechanism is provided. We show that the conformational switch from 4β+α to 3-α structure can occur via a single amino acid substitution. On one side of the switch point, the 4β+α fold is >90% populated (pH 7.2, 20 °C). A single mutation switches the conformation to the 3-α fold, which is >90% populated (pH 7.2, 20 °C). We further show that a bifunctional protein exists at the switch point with affinity for both IgG and albumin.
Related Links	http://dx.doi.org/10.1073/pnas.0906408106
Ending Page	21154
Page Count	6
Starting Page	21149
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	50
Volume Number	106
Language	English
Publisher	National Academy of Sciences
Publisher Date	2009-12-15
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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