Mutations can cause light chains to be too stable or too unstable to form amyloid fibrils

Marta Marin-Argany, Jofre Güell-Bosch, Luis M. Blancas-Mejía, Sandra Villegas, Marina Ramirez-Alvarado

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Light chain (AL) amyloidosis is an incurable human disease, where the amyloid precursor is a misfolding-prone immunoglobulin light-chain. Here, we identify the role of somatic mutations in the structure, stability and in vitro fibril formation for an amyloidogenic AL-12 protein by restoring four nonconservative mutations to their germline (wild-type) sequence. The single restorative mutations do not affect significantly the native structure, the unfolding pathway, and the reversibility of the protein. However, certain mutations either decrease (H32Y and H70D) or increase (R65S and Q96Y) the protein thermal stability. Interestingly, the most and the least stable mutants, Q96Y and H32Y, do not form amyloid fibrils under physiological conditions. Thus, Q96 and H32 are key residues for AL-12 stability and fibril formation and restoring them to the wild-type residues preclude amyloid formation. The mutants whose equilibrium is shifted to either the native or unfolded states barely sample transient partially folded states, and therefore do not form fibrils. These results agree with previous observations by our laboratory and others that amyloid formation occurs because of the sampling of partially folded states found within the unfolding transition (Blancas-Mejia and Ramirez-Alvarado, Ann Rev Biochem 2013;82:745–774). Here we provide a new insight on the AL amyloidosis mechanism by demonstrating that AL-12 does not follow the established thermodynamic hypothesis of amyloid formation. In this hypothesis, thermodynamically unstable proteins are more prone to amyloid formation. Here we show that within a thermal stability range, the most stable protein in this study is the most amyloidogenic protein.

Original languageEnglish (US)
Pages (from-to)1829-1840
Number of pages12
JournalProtein Science
DOIs
StatePublished - 2015

Fingerprint

Amyloid
Light
Mutation
Amyloidosis
Proteins
Thermodynamic stability
Hot Temperature
Immunoglobulin Light Chains
Amyloidogenic Proteins
Protein Stability
Thermodynamics
Sampling

Keywords

  • aggregation
  • immunoglobulin fold
  • light chain amyloidosis
  • protein misfolding
  • somatic mutations
  • thermodynamics

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Mutations can cause light chains to be too stable or too unstable to form amyloid fibrils. / Marin-Argany, Marta; Güell-Bosch, Jofre; Blancas-Mejía, Luis M.; Villegas, Sandra; Ramirez-Alvarado, Marina.

In: Protein Science, 2015, p. 1829-1840.

Research output: Contribution to journalArticle

Marin-Argany, Marta ; Güell-Bosch, Jofre ; Blancas-Mejía, Luis M. ; Villegas, Sandra ; Ramirez-Alvarado, Marina. / Mutations can cause light chains to be too stable or too unstable to form amyloid fibrils. In: Protein Science. 2015 ; pp. 1829-1840.
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