A single mutation in an SH3 domain increases amyloid aggregation by accelerating nucleation, but not by destabilizing thermodynamically the native state.


Abstract

We investigated the relationship between thermodynamic stability and amyloid aggregation propensity for a set of single mutants of the alpha-spectrin SH3 domain (Spc-SH3). Whilst mutations destabilizing the domain at position 56 did not enhance fibrillation, the N47A mutation increased the rate of amyloid fibril formation by 10-fold. Even under conditions of identical thermodynamic stability, the aggregation rate was much higher for the N47A mutant than for the WT domain. We conclude that the N47A mutation does not change the apparent mechanism of fibrillation or the morphology of the amyloid fibrils, and that its amyloidogenic property is due to its effect upon the rate of the conformational events leading to nucleation and not to its overall destabilizing effect. Study holds ProTherm entries: 24940, 24941, 24942, 24943, 24944, 24945, 24946, 24947, 24948, 24949, 24950, 24951, 24952, 24953, 24954 Extra Details: Amyloid; Thermodynamics; Protein stability; Differential scanning calorimetry Dynamic light scattering

Submission Details

ID: 7kVZoDD74

Submitter: Connie Wang

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

Version: 1

Publication Details
Varela L;Morel B;Azuaga AI;Conejero-Lara F,FEBS Lett. (2009) A single mutation in an SH3 domain increases amyloid aggregation by accelerating nucleation, but not by destabilizing thermodynamically the native state. PMID:19183554
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
3THK 2011-08-19T00:00:00+0000 1.7 Structure of SH3 chimera with a type II ligand linked to the chain C-terminal
2FOT 2006-01-13T00:00:00+0000 2.45 Crystal structure of the complex between calmodulin and alphaII-spectrin
3F31 2008-10-30T00:00:00+0000 2.3 Crystal Structure of the N-terminal region of AlphaII-spectrin Tetramerization Domain
3FB2 2008-11-18T00:00:00+0000 2.3 Crystal structure of the human brain alpha spectrin repeats 15 and 16. Northeast Structural Genomics Consortium target HR5563a.
5FW9 2016-02-12T00:00:00+0000 1.55 Human Spectrin SH3 domain D48G, E7Y, K60Y
5FWB 2016-02-12T00:00:00+0000 1.5 Human Spectrin SH3 domain D48G, E7F, K60F
5FWC 2016-02-12T00:00:00+0000 1.4 Human Spectrin SH3 domain D48G, E7A, K60A
6ZEH 2020-06-16T00:00:00+0000 1.3 Structure of PP1-spectrin alpha II chimera [PP1(7-304) + linker (G/S)x9 + spectrin alpha II (1025-1039)] bound to Phactr1 (516-580)
1AEY 1997-03-02T00:00:00+0000 0 ALPHA-SPECTRIN SRC HOMOLOGY 3 DOMAIN, SOLUTION NMR, 15 STRUCTURES
1AJ3 1997-05-14T00:00:00+0000 0 SOLUTION STRUCTURE OF THE SPECTRIN REPEAT, NMR, 20 STRUCTURES

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
100.0 Spectrin alpha chain, non-erythrocytic 1 P07751 SPTN1_CHICK
100.0 Spectrin alpha chain, non-erythrocytic 1 Q13813 SPTN1_HUMAN
100.0 Spectrin alpha chain, non-erythrocytic 1 P16546 SPTN1_MOUSE
100.0 Spectrin alpha chain, non-erythrocytic 1 P16086 SPTN1_RAT