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
2M8I 2014-04-09 Structure of Pin1 WW domain
5GPH 2017-08-09 Solution structure of the Pin1-PPIase (S138A) mutant
1I8G 2001-07-18 SOLUTION STRUCTURE OF PIN1 WW DOMAIN COMPLEXED WITH CDC25 PHOSPHOTHREONINE PEPTIDE
1NMV 2003-08-12 Solution structure of human Pin1
2M9J 2013-06-26 NMR solution structure of Pin1 WW domain mutant 6-1g
2N1O 2015-10-28 PIN1 WW domain in complex with a phosphorylated CPEB1 derived peptide
2M9F 2013-06-26 NMR solution structure of Pin1 WW domain mutant 5-1g
2RUD 2014-12-17 Solution structure of the peptidyl prolyl cis-trans isomerase domain of C113D mutant human Pin1 with sulfate ion
1NMW 2003-07-15 Solution structure of the PPIase domain of human Pin1
2RUR 2016-01-06 Solution structure of Human Pin1 PPIase C113S mutant
2M9I 2013-06-26 NMR solution structure of Pin1 WW domain variant 6-1
2RUQ 2016-01-06 solution structure of human Pin1 PPIase mutant C113A
2M9E 2013-06-26 NMR solution structure of Pin1 WW domain mutant 5-1
2LB3 2011-07-06 Structure of the WW domain of PIN1 in complex with a human phosphorylated Smad3 derived peptide
2M8J 2014-04-09 Structure of Pin1 WW domain phospho-mimic S16E
2KCF 2009-01-13 The NMR solution structure of the isolated Apo Pin1 WW domain
1I6C 2001-07-18 SOLUTION STRUCTURE OF PIN1 WW DOMAIN
1I8H 2001-07-18 SOLUTION STRUCTURE OF PIN1 WW DOMAIN COMPLEXED WITH HUMAN TAU PHOSPHOTHREONINE PEPTIDE
2KBU 2009-07-07 NMR solution structure of Pin1 WW domain mutant with beta turn mimic at position 12
2RUC 2014-12-17 Solution structure of the peptidyl prolyl cis-trans isomerase domain of human Pin1 with sulfate ion
3I6C 2010-04-21 1.3 Structure-Based Design of Novel PIN1 Inhibitors (II)
4TNS 2015-04-08 1.33 Structure of Pin1 PPIase domain bound with all-trans retinoic acid
1PIN 1998-10-14 1.35 PIN1 PEPTIDYL-PROLYL CIS-TRANS ISOMERASE FROM HOMO SAPIENS
3TC5 2011-08-31 1.4 Selective targeting of disease-relevant protein binding domains by O-phosphorylated natural product derivatives
2ITK 2007-05-22 1.45 human Pin1 bound to D-PEPTIDE
2ZQT 2009-08-25 1.46 Crystal structure of a mutant PIN1 PEPTIDYL-PROLYL CIS-TRANS ISOMERASE
2Q5A 2007-06-26 1.5 human Pin1 bound to L-PEPTIDE
5VTJ 2018-02-21 1.5 Structure of Pin1 WW Domain Sequence 1 Substituted with [S,S]ACPC
2F21 2006-06-20 1.5 human Pin1 Fip mutant
6DUN 2019-03-06 1.59 Crystal Structure Analysis of PIN1
3WH0 2014-10-15 1.6 Structure of Pin1 Complex with 18-crown-6
4U86 2015-04-08 1.6 Human Pin1 with cysteine sulfonic acid 113
4U85 2015-04-08 1.7 Human Pin1 with cysteine sulfinic acid 113
4TYO 2014-08-20 1.75 PPIase in complex with a non-phosphate small molecule inhibitor.
3NTP 2012-01-04 1.76 Human Pin1 complexed with reduced amide inhibitor
4U84 2015-04-08 1.78 Human Pin1 with S-hydroxyl-cysteine 113
5VTI 2018-02-21 1.8 Structure of Pin1 WW Domain Sequence 3 with [R,R]-ACPC Loop Substitution
2XP4 2011-01-12 1.8 DISCOVERY OF CELL-ACTIVE PHENYL-IMIDAZOLE PIN1 INHIBITORS BY STRUCTURE-GUIDED FRAGMENT EVOLUTION
1F8A 2000-08-23 1.84 STRUCTURAL BASIS FOR THE PHOSPHOSERINE-PROLINE RECOGNITION BY GROUP IV WW DOMAINS
5UY9 2017-04-26 1.85 Prolyl isomerase Pin1 R14A mutant bound with Brd4 peptide
3IK8 2009-09-22 1.85 Structure-Based Design of Novel PIN1 Inhibitors (I)
3IKG 2009-09-22 1.86 Structure-Based Design of Novel PIN1 Inhibitors (I)
3JYJ 2010-04-07 1.87 Structure-Based Design of Novel PIN1 Inhibitors (II)
4QIB 2015-02-04 1.87 Oxidation-Mediated Inhibition of the Peptidyl-Prolyl Isomerase Pin1
3OOB 2011-08-17 1.89 Structural and functional insights of directly targeting Pin1 by Epigallocatechin-3-gallate
2XP9 2011-01-12 1.9 DISCOVERY OF CELL-ACTIVE PHENYL-IMIDAZOLE PIN1 INHIBITORS BY STRUCTURE-GUIDED FRAGMENT EVOLUTION
2XPA 2011-01-12 1.9 DISCOVERY OF CELL-ACTIVE PHENYL-IMIDAZOLE PIN1 INHIBITORS BY STRUCTURE-GUIDED FRAGMENT EVOLUTION
1ZCN 2006-06-20 1.9 human Pin1 Ng mutant
2ZQS 2009-08-25 1.9 Crystal structure of a mutant PIN1 PEPTIDYL-PROLYL CIS-TRANS ISOMERASE
2XP5 2011-01-12 1.9 DISCOVERY OF CELL-ACTIVE PHENYL-IMIDAZOLE PIN1 INHIBITORS BY STRUCTURE-GUIDED FRAGMENT EVOLUTION
2XP6 2011-01-12 1.9 DISCOVERY OF CELL-ACTIVE PHENYL-IMIDAZOLE PIN1 INHIBITORS BY STRUCTURE-GUIDED FRAGMENT EVOLUTION
5B3Y 2016-10-26 1.9 Crystal structure of hPin1 WW domain (5-23) fused with maltose-binding protein
3KAG 2009-12-22 1.9 Structure-guided design of alpha-amino acid-derived Pin1 inhibitors
3KCE 2009-12-22 1.9 Structure-guided design of alpha-amino acid-derived Pin1 inhibitors
3KAI 2009-12-22 1.9 Structure-guided design of alpha-amino acid-derived Pin1 inhibitors
3KAD 2009-12-22 1.95 Structure-guided design of alpha-amino acid-derived Pin1 inhibitors
5VTK 2018-02-21 1.99 Structure of Pin1 WW Domain Variant 1 with beta3-Ser Loop Substitution
3IKD 2009-09-22 2.0 Structure-Based Design of Novel PIN1 Inhibitors (I)
2XP7 2011-01-12 2.0 DISCOVERY OF CELL-ACTIVE PHENYL-IMIDAZOLE PIN1 INHIBITORS BY STRUCTURE-GUIDED FRAGMENT EVOLUTION
5BMY 2016-10-26 2.0 Crystal structure of hPin1 WW domain (5-21) fused with maltose-binding protein
2XPB 2011-01-12 2.0 DISCOVERY OF CELL-ACTIVE PHENYL-IMIDAZOLE PIN1 INHIBITORS BY STRUCTURE-GUIDED FRAGMENT EVOLUTION
3KAC 2009-12-22 2.0 Structure-guided design of alpha-amino acid-derived Pin1 inhibitors
2ZR4 2009-08-25 2.0 Crystal structure of a mutant PIN1 peptidyl-prolyl cis-trans isomerase
2XP3 2011-01-12 2.0 DISCOVERY OF CELL-ACTIVE PHENYL-IMIDAZOLE PIN1 INHIBITORS BY STRUCTURE-GUIDED FRAGMENT EVOLUTION
3TCZ 2012-06-20 2.1 Human Pin1 bound to cis peptidomimetic inhibitor
2XP8 2011-01-12 2.1 DISCOVERY OF CELL-ACTIVE PHENYL-IMIDAZOLE PIN1 INHIBITORS BY STRUCTURE-GUIDED FRAGMENT EVOLUTION
3KAB 2009-12-22 2.19 Structure-guided design of alpha-amino acid-derived Pin1 inhibitors
4GWT 2013-10-16 2.25 Structure of racemic Pin1 WW domain cocrystallized with DL-malic acid
3TDB 2012-06-27 2.27 Human Pin1 bound to trans peptidomimetic inhibitor
3KAH 2009-12-22 2.3 Structure-guided design of alpha-amino acid-derived Pin1 inhibitors
3ODK 2010-10-27 2.3 Discovery of cell-active phenyl-imidazole Pin1 inhibitors by structure-guided fragment evolution
5B3Z 2016-10-26 2.3 Crystal structure of hPin1 WW domain (5-39) fused with maltose-binding protein
3KAF 2009-12-22 2.3 Structure-guided design of alpha-amino acid-derived Pin1 inhibitors
5B3W 2016-10-26 2.4 Crystal structure of hPin1 WW domain (5-15) fused with maltose-binding protein in C2221 form
5B3X 2016-10-26 2.4 Crystal structure of hPin1 WW domain (5-15) fused with maltose-binding protein in P41212 form
2ZQV 2009-08-25 2.5 Crystal structure of a mutant PIN1 PEPTIDYL-PROLYL CIS-TRANS ISOMERASE
2ZQU 2009-08-25 2.5 Crystal structure of a mutant PIN1 PEPTIDYL-PROLYL CIS-TRANS ISOMERASE
2ZR5 2009-08-25 2.6 Crystal structure of a mutant PIN1 peptidyl-prolyl cis-trans isomerase
4GWV 2013-10-16 3.05 Structure of racemic Pin1 WW domain cocrystallized with tri-ammonium citrate
2ZR6 2009-08-25 3.2 Crystal structure of a mutant PIN1 peptidyl-prolyl cis-trans isomerase

Relevant UniProtKB Entries

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