Structure-function-folding relationship in a WW domain.


Abstract

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

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
1F8A 2000-06-29T00:00:00+0000 1.84 STRUCTURAL BASIS FOR THE PHOSPHOSERINE-PROLINE RECOGNITION BY GROUP IV WW DOMAINS
1I6C 2001-03-02T00:00:00+0000 0 SOLUTION STRUCTURE OF PIN1 WW DOMAIN
1I8G 2001-03-14T00:00:00+0000 0 SOLUTION STRUCTURE OF PIN1 WW DOMAIN COMPLEXED WITH CDC25 PHOSPHOTHREONINE PEPTIDE
1I8H 2001-03-14T00:00:00+0000 0 SOLUTION STRUCTURE OF PIN1 WW DOMAIN COMPLEXED WITH HUMAN TAU PHOSPHOTHREONINE PEPTIDE
1NMV 2003-01-11T00:00:00+0000 0 Solution structure of human Pin1
1NMW 2003-01-12T00:00:00+0000 0 Solution structure of the PPIase domain of human Pin1
1PIN 1998-06-21T00:00:00+0000 1.35 PIN1 PEPTIDYL-PROLYL CIS-TRANS ISOMERASE FROM HOMO SAPIENS
1ZCN 2005-04-12T00:00:00+0000 1.9 human Pin1 Ng mutant
2F21 2005-11-15T00:00:00+0000 1.5 human Pin1 Fip mutant
2ITK 2006-10-19T00:00:00+0000 1.45 human Pin1 bound to D-PEPTIDE

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
100.0 Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 Q13526 PIN1_HUMAN
99.4 Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 Q4R383 PIN1_MACFA
98.2 Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 Q5BIN5 PIN1_BOVIN
95.2 Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 Q9QUR7 PIN1_MOUSE
90.5 Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 O15428 PINL_HUMAN