The denatured state dictates the topology of two proteins with almost identical sequence but different native structure and function.

Printer-friendly versionPrinter-friendly versionPDF versionPDF version
TitleThe denatured state dictates the topology of two proteins with almost identical sequence but different native structure and function.
Publication TypeJournal Article
Year of Publication2011
AuthorsMorrone, A, McCully, ME, Bryan, PN, Brunori, M, Daggett, V, Gianni, S, Travaglini-Allocatelli, C
JournalJ Biol Chem
Volume286
Issue5
Pagination3863-72
Date Published2011 Feb 4
ISSN1083-351X
KeywordsAmino Acid Sequence, Hydrogen-Ion Concentration, Molecular Dynamics Simulation, Protein Conformation, Protein Denaturation, Protein Engineering, Protein Folding, Proteins
Abstract

The protein folding problem is often studied by comparing the mechanisms of proteins sharing the same structure but different sequence. The recent design of the two proteins G(A)88 and G(B)88, displaying different structures and functions while sharing 88% sequence identity (49 out of 56 amino acids), allows the unique opportunity for a complementary approach. At which stage of its folding pathway does a protein commit to a given topology? Which residues are crucial in directing folding mechanisms to a given structure? By using a combination of biophysical and computational techniques, we have characterized the folding of both G(A)88 and G(B)88. We show that, contrary to expectation, G(B)88, characterized by a native α+β fold, displays in the denatured state a content of native-like helical structure greater than G(A)88, which is all-α in its native state. Both experiments and simulations indicate that such residual structure may be tuned by changing pH. Thus, despite the high sequence identity, the folding pathways for these two proteins appear to diverge as early as in the denatured state. Our results suggest a mechanism whereby protein topology is committed very early along the folding pathway, being imprinted in the residual structure of the denatured state.

DOI10.1074/jbc.M110.155911
Alternate JournalJ. Biol. Chem.
PubMed ID21118804
PubMed Central IDPMC3030387
Grant ListGM062154 / GM / NIGMS NIH HHS / United States
GM50789 / GM / NIGMS NIH HHS / United States