Hydrophobic core packing in the SH3 domain folding transition state.


Abstract

How tightly packed is the hydrophobic core of a folding transition state structure? We have addressed this question by characterizing the effects on folding kinetics of > 40 substitutions of both large and small amino acids in the hydrophobic core of the Fyn SH3 domain. Our results show that residues at three positions, which we designate as the 'core folding nucleus', are tightly packed in the transition state, and substitutions at these positions cause the largest changes in the folding rate. The other six positions examined appear to be loosely packed; thus, substitutions at these positions with larger hydrophobic residues generally accelerate folding, presumably by increasing the rate of nonspecific hydrophobic collapse. Surprisingly, the folding rate can be greatly accelerated by residues that also significantly destabilize the native state structure. Furthermore, mutants with identical thermodynamic stability can differ by up to 55-fold in their folding rates. These results highlight the importance of hydrophobic core composition, as opposed to only topology, in determining the folding rate of a protein. They also provide a new explanation for the 'abnormal' phi-values observed in many protein folding kinetics studies. Study holds ProTherm entries: 12771, 12772, 12773, 12774, 12775, 12776, 12777, 12778, 12779, 12780, 12781, 12782, 12783, 12784, 12785, 12786, 12787, 12788, 12789, 12790, 12791, 12792, 12793, 12794, 12795, 12796, 12797, 12798, 12799, 12800, 12801, 12802, 12803, 12804, 12805, 12806, 12807, 12808, 12809, 12810, 12811, 12812 Extra Details: SH3 domain; 0.2 mM EDTA was added in the experiment hydrophobic core packing; core folding nucleus; folding rate;,transition state

Submission Details

ID: 88FrYQYy3

Submitter: Connie Wang

Submission Date: April 24, 2018, 8:44 p.m.

Version: 1

Publication Details
Northey JG;Di Nardo AA;Davidson AR,Nat. Struct. Biol. (2002) Hydrophobic core packing in the SH3 domain folding transition state. PMID:11786916
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
3UF4 2011-10-31T00:00:00+0000 1.98 Crystal structure of a SH3 and SH2 domains of FYN protein (Proto-concogene Tyrosine-protein kinase Fyn) from Mus musculus at 1.98 A resolution
2L2P 2010-08-25T00:00:00+0000 0 Folding Intermediate of the Fyn SH3 A39V/N53P/V55L from NMR Relaxation Dispersion Experiments
2LP5 2012-02-06T00:00:00+0000 0 Native Structure of the Fyn SH3 A39V/N53P/V55L
3CQT 2008-04-03T00:00:00+0000 1.6 N53I V55L MUTANT of FYN SH3 DOMAIN
1A0N 1997-12-05T00:00:00+0000 0 NMR STUDY OF THE SH3 DOMAIN FROM FYN PROTO-ONCOGENE TYROSINE KINASE COMPLEXED WITH THE SYNTHETIC PEPTIDE P2L CORRESPONDING TO RESIDUES 91-104 OF THE P85 SUBUNIT OF PI3-KINASE, FAMILY OF 25 STRUCTURES
1AOT 1997-07-10T00:00:00+0000 0 NMR STRUCTURE OF THE FYN SH2 DOMAIN COMPLEXED WITH A PHOSPHOTYROSYL PEPTIDE, MINIMIZED AVERAGE STRUCTURE
1AOU 1997-07-10T00:00:00+0000 0 NMR STRUCTURE OF THE FYN SH2 DOMAIN COMPLEXED WITH A PHOSPHOTYROSYL PEPTIDE, 22 STRUCTURES
1AVZ 1997-09-23T00:00:00+0000 3.0 V-1 NEF PROTEIN IN COMPLEX WITH WILD TYPE FYN SH3 DOMAIN
1AZG 1997-11-18T00:00:00+0000 0 NMR STUDY OF THE SH3 DOMAIN FROM FYN PROTO-ONCOGENE TYROSINE KINASE KINASE COMPLEXED WITH THE SYNTHETIC PEPTIDE P2L CORRESPONDING TO RESIDUES 91-104 OF THE P85 SUBUNIT OF PI3-KINASE, MINIMIZED AVERAGE (PROBMAP) STRUCTURE
1EFN 1996-06-29T00:00:00+0000 2.5 HIV-1 NEF PROTEIN IN COMPLEX WITH R96I MUTANT FYN SH3 DOMAIN

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
100.0 Tyrosine-protein kinase Fyn P06241 FYN_HUMAN
99.6 Tyrosine-protein kinase Fyn A0JNB0 FYN_BOVIN
99.6 Tyrosine-protein kinase Fyn Q62844 FYN_RAT
99.4 Tyrosine-protein kinase Fyn A1Y2K1 FYN_PIG
99.4 Tyrosine-protein kinase Fyn P39688 FYN_MOUSE
96.8 Tyrosine-protein kinase Fyn P13406 FYN_XENLA
92.6 Tyrosine-protein kinase Fyn P27446 FYN_XIPHE
92.4 Tyrosine-protein kinase Fyn Q6EWH2 FYNA_DANRE
90.6 Tyrosine-protein kinase Fyn F1RDG9 FYNB_DANRE
92.4 Tyrosine-protein kinase Fyn Q05876 FYN_CHICK