Structure-function-folding relationship in a WW domain.


Protein folding barriers result from a combination of factors including unavoidable energetic frustration from nonnative interactions, natural variation and selection of the amino acid sequence for function, and/or selection pressure against aggregation. The rate-limiting step for human Pin1 WW domain folding is the formation of the loop 1 substructure. The native conformation of this six-residue loop positions side chains that are important for mediating protein-protein interactions through the binding of Pro-rich sequences. Replacement of the wild-type loop 1 primary structure by shorter sequences with a high propensity to fold into a type-I' beta-turn conformation or the statistically preferred type-I G1 bulge conformation accelerates WW domain folding by almost an order of magnitude and increases thermodynamic stability. However, loop engineering to optimize folding energetics has a significant downside: it effectively eliminates WW domain function according to ligand-binding studies. The energetic contribution of loop 1 to ligand binding appears to have evolved at the expense of fast folding and additional protein stability. Thus, the two-state barrier exhibited by the wild-type human Pin1 WW domain principally results from functional requirements, rather than from physical constraints inherent to even the most efficient loop formation process. Study holds ProTherm entries: 22161, 22162, 22163, 22164, 22165, 22166, 22167, 22168, 22169, 22170, 22171 Extra Details: variant 1, 4:6 loop (Sequence: KLPPGWEKRMSRSSGRVYYFNHITNASQWERPSG). beta-turn; ligand binding; protein folding; beta-sheet; protein function

Submission Details

ID: FB6jE4Er

Submitter: Connie Wang

Submission Date: April 24, 2018, 8:53 p.m.

Version: 1

Publication Details
J├Ąger M;Zhang Y;Bieschke J;Nguyen H;Dendle M;Bowman ME;Noel JP;Gruebele M;Kelly JW,Proc. Natl. Acad. Sci. U.S.A. (2006) Structure-function-folding relationship in a WW domain. PMID:16807295
Additional Information

Sequence Assay Result Units