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
2JMA 2007-04-24 R21A Spc-SH3:P41 complex
2KR3 2010-09-15 Solution structure of SHA-D
2RMO 2008-09-30 Solution structure of alpha-spectrin_SH3-bergerac from Chicken
2JMC 2007-04-24 Chimer between Spc-SH3 and P41
2JM8 2007-04-24 R21A Spc-SH3 free
2LJ3 2011-12-07 PFBD: High-throughput Strategy of Backbone fold Determination for small well-folded proteins in less than a day
2KXD 2011-04-20 The structure of SH3-F2
1AEY 1997-05-15 ALPHA-SPECTRIN SRC HOMOLOGY 3 DOMAIN, SOLUTION NMR, 15 STRUCTURES
2ROT 2009-04-28 Structure of chimeric variant of SH3 domain- SHH
2JM9 2007-04-24 R21A Spc-SH3 bound
1AJ3 1997-07-07 SOLUTION STRUCTURE OF THE SPECTRIN REPEAT, NMR, 20 STRUCTURES
1M8M 2002-11-20 SOLID-STATE MAS NMR STRUCTURE OF THE A-SPECTRIN SH3 DOMAIN
3NGP 2010-09-08 1.08 High resolution structure of alpha-spectrin SH3 domain mutant with a redesigned core
3M0U 2011-01-19 1.1 Crystal Structure of the R21D mutant of alpha-spectrin SH3 domain. Hexagonal crystal obtained in sodium formate at pH 6.5.
3M0R 2011-01-19 1.1 Crystal Structure of the R21D mutant of alpha-spectrin SH3 domain. Crystal obtained in ammonium sulphate at pH 6.
1G2B 2000-11-01 1.12 ALPHA-SPECTRIN SRC HOMOLOGY 3 DOMAIN, CIRCULAR PERMUTANT, CUT AT N47-D48
5IHK 2017-03-29 1.35 Crystal Structure of the alpha spectrin SH3 domain mutant N47A
5FWC 2016-12-28 1.4 Human Spectrin SH3 domain D48G, E7A, K60A
5IHI 2017-03-29 1.45 Crystal Structure of the alpha spectrin SH3 domain double mutant V46G-D48G
3I9Q 2009-12-15 1.45 Crystal Structure of the triple mutant S19G-P20D-R21S of alpha spectrin SH3 domain
1U06 2005-01-13 1.49 crystal structure of chicken alpha-spectrin SH3 domain
5IHN 2017-03-29 1.5 Crystal Structure of the alpha spectrin SH3 domain mutant N47G
5FWB 2016-12-28 1.5 Human Spectrin SH3 domain D48G, E7F, K60F
4F17 2013-05-08 1.55 Crystal Structure of the alpha spectrin SH3 domain at pH 9
5FW9 2016-12-28 1.55 Human Spectrin SH3 domain D48G, E7Y, K60Y
3M0S 2011-01-19 1.6 Crystal Structure of the R21D mutant of alpha-spectrin SH3 domain. Crystal obtained in ammonium sulphate at pH 7
2F2X 2006-10-31 1.6 alpha-spectrin SH3 domain R21G mutant
3THK 2011-11-23 1.7 Structure of SH3 chimera with a type II ligand linked to the chain C-terminal
2F2W 2006-10-31 1.7 alpha-spectrin SH3 domain R21A mutant
3M0T 2011-01-19 1.7 Crystal Structure of the R21D mutant of alpha-spectrin SH3 domain. Crystal obtained in ammonium sulphate at pH 9.
3M0Q 2011-01-19 1.75 Crystal Structure of the R21D mutant of alpha-spectrin SH3 domain. Crystal obtained in ammonium sulphate at pH 5.
1TUD 1996-08-01 1.77 ALPHA-SPECTRIN SRC HOMOLOGY 3 DOMAIN, CIRCULAR PERMUTANT, CUT AT N47-D48
1PWT 1999-05-11 1.77 THERMODYNAMIC ANALYSIS OF ALPHA-SPECTRIN SH3 AND TWO OF ITS CIRCULAR PERMUTANTS WITH DIFFERENT LOOP LENGTHS: DISCERNING THE REASONS FOR RAPID FOLDING IN PROTEINS
1SHG 1993-10-31 1.8 CRYSTAL STRUCTURE OF A SRC-HOMOLOGY 3 (SH3) DOMAIN
1QKX 2000-12-15 1.8 Alpha-spectrin Src Homology 3 domain, N47A mutant in the distal loop.
2NUZ 2007-05-15 1.85 crystal structure of alpha spectrin SH3 domain measured at room temperature
2F2V 2006-10-31 1.85 alpha-spectrin SH3 domain A56G mutant
2OAW 2008-04-08 1.9 Structure of SHH variant of 'Bergerac' chimera of spectrin SH3
4F16 2013-05-08 1.93 Crystal Structure of the alpha spectrin SH3 domain at pH 5
1HD3 2001-11-01 1.98 A-SPECTRIN SH3 DOMAIN F52Y MUTANT
1CUN 1999-10-06 2.0 CRYSTAL STRUCTURE OF REPEATS 16 AND 17 OF CHICKEN BRAIN ALPHA SPECTRIN
1QKW 2000-08-18 2.0 Alpha-spectrin Src Homology 3 domain, N47G mutant in the distal loop.
1U5P 2004-10-19 2.0 Crystal Structure of Repeats 15 and 16 of Chicken Brain Alpha Spectrin
1BK2 1999-02-16 2.01 A-SPECTRIN SH3 DOMAIN D48G MUTANT
1E6H 2002-05-23 2.01 A-SPECTRIN SH3 DOMAIN A11V, M25I, V44I, V58L MUTANTS
1TUC 1996-08-01 2.02 ALPHA-SPECTRIN SRC HOMOLOGY 3 DOMAIN, CIRCULAR PERMUTANT, CUT AT S19-P20
3F31 2009-10-13 2.3 Crystal Structure of the N-terminal region of AlphaII-spectrin Tetramerization Domain
1NEG 2003-01-14 2.3 Crystal Structure Analysis of N-and C-terminal labeled SH3-domain of alpha-Chicken Spectrin
1E6G 2002-05-23 2.3 A-SPECTRIN SH3 DOMAIN A11V, V23L, M25I, V53I, V58L MUTANT
3FB2 2008-11-25 2.3 Crystal structure of the human brain alpha spectrin repeats 15 and 16. Northeast Structural Genomics Consortium target HR5563a.
2FOT 2006-09-05 2.45 Crystal structure of the complex between calmodulin and alphaII-spectrin
1U4Q 2004-10-19 2.5 Crystal Structure of Repeats 15, 16 and 17 of Chicken Brain Alpha Spectrin
2CDT 2007-02-20 2.54 alpha-SPECTRIN SH3 DOMAIN A56S MUTANT
1UUE 2004-02-19 2.6 a-SPECTRIN SH3 DOMAIN (V44T, D48G MUTANT)
3M0P 2011-01-19 2.6 Crystal Structure of the R21D mutant of alpha-spectrin SH3 domain. Crystal obtained in ammonium sulphate at pH 4.
1H8K 2002-05-23 2.7 A-SPECTRIN SH3 DOMAIN A11V, V23L, M25V, V53I, V58L MUTANT
1E7O 2003-05-21 3.2 A-SPECTRIN SH3 DOMAIN A11V, V23L, M25V, V44I, V58L MUTATIONS
5M6S 2017-01-11 4.8 folding intermediate of spectrin R16

Relevant UniProtKB Entries

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