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Recent Advances in Transthyretin Evolution, Structure and Biological Functions pp 201–214Cite as

Histidine 31: The Achilles' Heel of Human Transthyretin. Microheterogeneity is Not Enough to Understand the Molecular Causes of Amyloidogenicity

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Abstract

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 (β-strand B) and Ser46 (β-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.

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Abbreviations

ATTR:

Amyloidogenic transthyretin

CA:

Carrier ampholytes

DTT:

Dithiothreitol

FAP:

Familial amyloidotic polyneuropathy

HEPES:

2-(4-(2-Hydroxyethyl)-1-piperazinyl)-ethanesulfonic acid

IEF:

Isoelectric focusing

MOPS:

3-(N-Morpholino)-propanesulfonic acid

PAGE:

Polyacrylamide gel electrophoresis

PIPES:

1,4-Piperazinediethane sulfonic acid

RBP:

Retinol-binding protein

SDS:

Sodium dodecylsulfate

TTR:

Transthyretin

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Acknowledgment

We appreciate the technical assistance of Pia Winter.

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Authors and Affiliations

  1. Justus-Liebig-University, Institute of Human Genetics, Schlangenzahl 14, D-35392, Giessen, Germany

    Klaus Altland

  2. School of Medical Sciences (building 223, level 2, rootm 51), RMIT University, 71, Bundoora, 3083, Victoria, Australia

    Samantha J. Richardson

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  1. Klaus Altland
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Correspondence to Klaus Altland .

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Editors and Affiliations

  1. School of Medical Sciences, RMIT University, Bundoora, VIC 3083, Bundoora West Campus, Australia

    Samantha J. Richardson

  2. Medical Research Institute, Hauptman-Woodward, 700 Elliott Street, Buffalo, NY, 14203, USA

    Vivian Cody

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Altland, K., Richardson, S.J. (2009). Histidine 31: The Achilles' Heel of Human Transthyretin. Microheterogeneity is Not Enough to Understand the Molecular Causes of Amyloidogenicity. In: Richardson, S.J., Cody, V. (eds) Recent Advances in Transthyretin Evolution, Structure and Biological Functions. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00646-3_13

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