Sequence determinants of thermodynamic stability in a WW domain--an all-beta-sheet protein.


Abstract

The stabilities of 66 sequence variants of the human Pin1 WW domain have been determined by equilibrium thermal denaturation experiments. All 34 residues composing the hPin1 WW three-stranded beta-sheet structure could be replaced one at a time with at least one different natural or non-natural amino acid residue without leading to an unfolded protein. Alanine substitutions at only four positions within the hPin1 WW domain lead to a partially or completely unfolded protein-in the absence of a physiological ligand. The side chains of these four residues form a conserved, partially solvent-inaccessible, continuous hydrophobic minicore comprising the N- and C-termini. Ala mutations at five other residues, three of which constitute the ligand binding patch on the concave side of the beta-sheet, significantly destabilize the hPin1 WW domain without leading to an unfolded protein. The remaining mutations affect protein stability only slightly, suggesting that only a small subset of side chain interactions within the hPin1 WW domain are mandatory for acquiring and maintaining a stable, cooperatively folded beta-sheet structure. Study holds ProTherm entries: 25101, 25102, 25103, 25104, 25105, 25106, 25107, 25108, 25109, 25110, 25111, 25112, 25113, 25114, 25115, 25116, 25117, 25118, 25119, 25120, 25121, 25122, 25123, 25124, 25125, 25126, 25127, 25128, 25129, 25130, 25131, 25132, 25133, 25134, 25135, 25136, 25137, 25138, 25139, 25140, 25141, 25142, 25143, 25144, 25145, 25146, 25147, 25148, 25149, 25150, 25151, 25152, 25153, 25154, 25155, 25156, 25157, 25158, 25159, 25160, 25161, 25162, 25163, 25164, 25165, 25166, 25167, 25168, 25169, 25170, 25171, 25172, 25173, 25174, 25175, 25176, 25177, 25178, 25179, 25180, 25181, 25182, 25183, 25184, 25185, 25186, 25187, 25188, 25189, 25190, 25191, 25192, 25193, 25194, 25195, 25196, 25197, 25198, 25199, 25200, 25201, 25202, 25203, 25204, 25205, 25206, 25207, 25208, 25209, 25210, 25211, 25212, 25213, 25214 Extra Details: WW domain; Ala scanning; Gly scanning; side chain mutagenesis; protein stability; protein folding; beta-sheet

Submission Details

ID: xT7jFTKE4

Submitter: Connie Wang

Submission Date: April 24, 2018, 8:55 p.m.

Version: 1

Publication Details
J├Ąger M;Dendle M;Kelly JW,Protein Sci. (2009) Sequence determinants of thermodynamic stability in a WW domain--an all-beta-sheet protein. PMID:19565466
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
2M9J 2013-06-26 NMR solution structure of Pin1 WW domain mutant 6-1g
2RUC 2014-12-17 Solution structure of the peptidyl prolyl cis-trans isomerase domain of human Pin1 with sulfate ion
1NMV 2003-08-12 Solution structure of human Pin1
1NMW 2003-07-15 Solution structure of the PPIase domain of human Pin1
2M8J 2014-04-09 Structure of Pin1 WW domain phospho-mimic S16E
2M9F 2013-06-26 NMR solution structure of Pin1 WW domain mutant 5-1g
5GPH 2017-08-09 Solution structure of the Pin1-PPIase (S138A) mutant
1I6C 2001-07-18 SOLUTION STRUCTURE OF PIN1 WW DOMAIN
2KBU 2009-07-07 NMR solution structure of Pin1 WW domain mutant with beta turn mimic at position 12
2N1O 2015-10-28 PIN1 WW domain in complex with a phosphorylated CPEB1 derived peptide
1I8G 2001-07-18 SOLUTION STRUCTURE OF PIN1 WW DOMAIN COMPLEXED WITH CDC25 PHOSPHOTHREONINE PEPTIDE
2LB3 2011-07-06 Structure of the WW domain of PIN1 in complex with a human phosphorylated Smad3 derived peptide
2M9I 2013-06-26 NMR solution structure of Pin1 WW domain variant 6-1
2RUD 2014-12-17 Solution structure of the peptidyl prolyl cis-trans isomerase domain of C113D mutant human Pin1 with sulfate ion
2M8I 2014-04-09 Structure of Pin1 WW domain
2M9E 2013-06-26 NMR solution structure of Pin1 WW domain mutant 5-1
2KCF 2009-01-13 The NMR solution structure of the isolated Apo Pin1 WW domain
2RUQ 2016-01-06 solution structure of human Pin1 PPIase mutant C113A
1I8H 2001-07-18 SOLUTION STRUCTURE OF PIN1 WW DOMAIN COMPLEXED WITH HUMAN TAU PHOSPHOTHREONINE PEPTIDE
2RUR 2016-01-06 Solution structure of Human Pin1 PPIase C113S mutant
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
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
2Q5A 2007-06-26 1.5 human Pin1 bound to L-PEPTIDE
6DUN 2019-03-06 1.59 Crystal Structure Analysis of PIN1
4U86 2015-04-08 1.6 Human Pin1 with cysteine sulfonic acid 113
3WH0 2014-10-15 1.6 Structure of Pin1 Complex with 18-crown-6
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
2XP4 2011-01-12 1.8 DISCOVERY OF CELL-ACTIVE PHENYL-IMIDAZOLE PIN1 INHIBITORS BY STRUCTURE-GUIDED FRAGMENT EVOLUTION
5VTI 2018-02-21 1.8 Structure of Pin1 WW Domain Sequence 3 with [R,R]-ACPC Loop Substitution
1F8A 2000-08-23 1.84 STRUCTURAL BASIS FOR THE PHOSPHOSERINE-PROLINE RECOGNITION BY GROUP IV WW DOMAINS
3IK8 2009-09-22 1.85 Structure-Based Design of Novel PIN1 Inhibitors (I)
5UY9 2017-04-26 1.85 Prolyl isomerase Pin1 R14A mutant bound with Brd4 peptide
3IKG 2009-09-22 1.86 Structure-Based Design of Novel PIN1 Inhibitors (I)
4QIB 2015-02-04 1.87 Oxidation-Mediated Inhibition of the Peptidyl-Prolyl Isomerase Pin1
3JYJ 2010-04-07 1.87 Structure-Based Design of Novel PIN1 Inhibitors (II)
3OOB 2011-08-17 1.89 Structural and functional insights of directly targeting Pin1 by Epigallocatechin-3-gallate
2XP5 2011-01-12 1.9 DISCOVERY OF CELL-ACTIVE PHENYL-IMIDAZOLE PIN1 INHIBITORS BY STRUCTURE-GUIDED FRAGMENT EVOLUTION
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
5B3Y 2016-10-26 1.9 Crystal structure of hPin1 WW domain (5-23) fused with maltose-binding protein
2ZQS 2009-08-25 1.9 Crystal structure of a mutant PIN1 PEPTIDYL-PROLYL CIS-TRANS ISOMERASE
2XP9 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
2XPA 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
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
2XP3 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
2XPB 2011-01-12 2.0 DISCOVERY OF CELL-ACTIVE PHENYL-IMIDAZOLE PIN1 INHIBITORS BY STRUCTURE-GUIDED FRAGMENT EVOLUTION
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
3IKD 2009-09-22 2.0 Structure-Based Design of Novel PIN1 Inhibitors (I)
2ZR4 2009-08-25 2.0 Crystal structure of a mutant PIN1 peptidyl-prolyl cis-trans isomerase
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
3ODK 2010-10-27 2.3 Discovery of cell-active phenyl-imidazole Pin1 inhibitors by structure-guided fragment evolution
3KAH 2009-12-22 2.3 Structure-guided design of alpha-amino acid-derived Pin1 inhibitors
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
5B3X 2016-10-26 2.4 Crystal structure of hPin1 WW domain (5-15) fused with maltose-binding protein in P41212 form
5B3W 2016-10-26 2.4 Crystal structure of hPin1 WW domain (5-15) fused with maltose-binding protein in C2221 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