Histidine 31: The Achilles' heel of human tranthyretin. Microheterogeneity is not enough to understand the molecular causes of amyloidogenicity

Altland, K and Richardson, S 2009, 'Histidine 31: The Achilles' heel of human tranthyretin. Microheterogeneity is not enough to understand the molecular causes of amyloidogenicity' in S.J. Richardson, V. Cody (ed.) Recent advances in transthyretin evolution, structure and biological functions, Springer-Verlag, Netherlands, pp. 201-214.


Document type: Book Chapter
Collection: Book Chapters

Title Histidine 31: The Achilles' heel of human tranthyretin. Microheterogeneity is not enough to understand the molecular causes of amyloidogenicity
Author(s) Altland, K
Richardson, S
Year 2009
Title of book Recent advances in transthyretin evolution, structure and biological functions
Publisher Springer-Verlag
Place of publication Netherlands
Editor(s) S.J. Richardson, V. Cody
Start page 201
End page 214
Subjects Medical Biochemistry: Proteins and Peptides (incl. Medical Proteomics)
Summary The microheterogeneity of human transthyretin (TTR) is mainly one of ligand and amino acid substitutions. These substitutions modify the conformational stability of monomers, dimers, and tetramers and may eventually result in unfolding-refolding transitions with the endpoint of amyloidosis. In this chapter we focus on a structural peculiarity of human TTR, i.e., a hydrogen bridge between His31 (beta-strand B) and Ser46 (beta-strand C), which appears to be the vulnerable site for changes of pH within a range (pH 7.4-6.5) observed under conditions of interstitial acidosis. We present arguments in favor of a cooperative interaction of all sites in the TTR monomer in modifying its conformational stability and reversible unfolding-refolding transitions which also affect the dimer and tetramer. We postulate that the unfolded monomer is the pool from which amyloidogenic aggregates are generated.
Copyright notice Springer-verlag 2009
DOI - identifier 10.1007/978-3-642-00646-3
ISBN 9783642006456
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