Thermodynamic modulation of light chain amyloid fibril formation.


Abstract

To obtain further insight into the pathogenesis of amyloidosis and develop therapeutic strategies to inhibit fibril formation we investigated: 1) the relationship between intrinsic physical properties (thermodynamic stability and hydrogen-deuterium (H-D) exchange rates) and the propensity of human immunoglobulin light chains to form amyloid fibrils in vitro; and 2) the effects of extrinsically modulating these properties on fibril formation. An amyloid-associated protein readily formed amyloid fibrils in vitro and had a lower free energy of unfolding than a homologous nonpathological protein, which did not form fibrils in vitro. H-D exchange was much faster for the pathological protein, suggesting it had a greater fraction of partially folded molecules. The thermodynamic stabilizer sucrose completely inhibited fibril formation by the pathological protein and shifted the values for its physical parameters to those measured for the nonpathological protein in buffer alone. Conversely, urea sufficiently destabilized the nonpathological protein such that its measured physical properties were equivalent to those of the pathological protein in buffer, and it formed fibrils. Thus, fibril formation by light chains is predominantly controlled by thermodynamic stability; and a rational strategy to inhibit amyloidosis is to design high affinity ligands that specifically increase the stability of the native protein. Study holds ProTherm entries: 6432, 6433, 6434, 6435, 6436, 6437, 6438, 6439, 6440, 6441, 6442, 6443 Extra Details: Bence Jones proteins, BIF therapeutic strategy; thermodynamic stability; amyloid fibril;,high affinity

Submission Details

ID: QmYP6cmN4

Submitter: Connie Wang

Submission Date: April 24, 2018, 8:32 p.m.

Version: 1

Publication Details
Kim Y;Wall JS;Meyer J;Murphy C;Randolph TW;Manning MC;Solomon A;Carpenter JF,J. Biol. Chem. (2000) Thermodynamic modulation of light chain amyloid fibril formation. PMID:10636846
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
2Q20 2008-04-08 1.3 Structure of the germline Vk1 O18/O8 light chain variable domain homodimer
1EEQ 2001-02-01 1.5 M4L/Y(27D)D/T94H Mutant of LEN
3CDC 2008-09-02 1.53 kI O18/O8 N34I/Y87H immunoglobulin light chain variable domain
3CDF 2008-09-02 1.53 kI O18/O8 Y87H immunoglobulin light chain variable domain
1EFQ 2001-02-09 1.6 Q38D mutant of LEN
1EEU 2001-02-03 1.6 M4L/Y(27D)D/Q89D/T94H mutant of LEN
4L1H 2014-06-04 1.68 Bence-Jones immunoglobulin REI variable portion with seven point mutations
1BWW 1998-10-07 1.7 BENCE-JONES IMMUNOGLOBULIN REI VARIABLE PORTION, T39K MUTANT
1B0W 1998-11-16 1.8 Structural comparison of amyloidogenic light chain dimer in two crystal forms with nonamyloidogenic counterparts
1QAC 2000-02-23 1.8 CHANGE IN DIMERIZATION MODE BY REMOVAL OF A SINGLE UNSATISFIED POLAR RESIDUE
1WTL 1994-11-01 1.9 COMPARISON OF CRYSTAL STRUCTURES OF TWO HOMOLOGOUS PROTEINS: STRUCTURAL ORIGIN OF ALTERED DOMAIN INTERACTIONS IN IMMUNOGLOBULIN LIGHT CHAIN DIMERS
1EK3 2001-03-06 1.9 KAPPA-4 IMMUNOGLOBULIN VL, REC
1LVE 1998-01-21 1.95 STRUCTURE OF THE VARIABLE DOMAIN OF HUMAN IMMUNOGLOBULIN K-4 LIGHT CHAIN LEN
3LVE 1999-05-18 2.0 LEN Q38E MUTANT: A DOMAIN FLIP FROM A SINGLE AMINO ACID SUBSTITUTION
1REI 1976-05-19 2.0 THE MOLECULAR STRUCTURE OF A DIMER COMPOSED OF THE VARIABLE PORTIONS OF THE BENCE-JONES PROTEIN REI REFINED AT 2.0 ANGSTROMS RESOLUTION
5LVE 2000-02-18 2.0 STRUCTURE OF THE VARIABLE DOMAIN OF HUMAN IMMUNOGLOBULIN K-4 LIGHT CHAIN LEN
1QP1 1999-06-17 2.06 KAPPA VARIABLE LIGHT CHAIN
1JV5 2002-01-09 2.2 Anti-blood group A Fv
4LVE 1999-05-18 2.3 LEN K30T MUTANT: A DOMAIN FLIP AS A RESULT OF A SINGLE AMINO ACID SUBSTITUTION
3CDY 2008-09-02 2.43 AL-09 H87Y, immunoglobulin light chain variable domain
2LVE 1999-05-18 2.7 RECOMBINANT LEN
1AR2 1997-11-12 2.8 DISULFIDE-FREE IMMUNOGLOBULIN FRAGMENT
4K07 2013-10-30 2.83 Crystal structure of the amyloid-forming immunoglobulin AL-103 cis-proline 95 mutant
5XP1 2017-08-02 2.88 Structure of monomeric mutant of REI immunoglobulin light chain variable domain crystallized at pH 6

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
100.0 Immunoglobulin kappa variable 1D-33 P01593 KVD33_HUMAN
100.0 Immunoglobulin kappa variable 1D-33 P01594 KV133_HUMAN
99.0 Immunoglobulin kappa variable 4-1 P06312 KV401_HUMAN