PDBsum entry 2trh

Transport

PDB id

2trh

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Contents

			Protein chain

					127 a.a. *

			Waters ×71

* Residue conservation analysis

PDB id:

2trh

Links

Name:

Transport

Title:

Tertiary structures of three amyloidogenic transthyretin variants and implications for amyloid fibril formation

Structure:

Transthyretin. Chain: a, b. Synonym: prealbumin. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Cell_line: hb101. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_cell_line: hb101.

Biol. unit:

Homo-Tetramer (from PDB file)

Resolution:

1.90Å

R-factor:

0.219

R-free:

0.299

Authors:

N.Schormann,J.R.Murrell,M.D.Benson

Key ref:

N.Schormann et al. (1998). Tertiary structures of amyloidogenic and non-amyloidogenic transthyretin variants: new model for amyloid fibril formation. Amyloid, 5, 175-187. PubMed id: 9818054

Date:

16-Oct-96

Release date:

21-Apr-97

PROCHECK

	Headers

	References

Protein chains

P02766 (TTHY_HUMAN) - Transthyretin from Homo sapiens

Seq: Struc:					147 a.a. 127 a.a.*

Key:

PfamA domain

Secondary structure

CATH domain

* PDB and UniProt seqs differ at 1 residue position (black cross)



		Enzyme reactions

Enzyme class:

E.C.?

[IntEnz] [ExPASy] [KEGG] [BRENDA]

	Amyloid 5:175-187 (1998)
PubMed id: 9818054

Tertiary structures of amyloidogenic and non-amyloidogenic transthyretin variants: new model for amyloid fibril formation.
N.Schormann, J.R.Murrell, M.D.Benson.

ABSTRACT

The most common form of hereditary systemic amyloidosis is familial amyloidotic polyneuropathy associated with single amino acid changes in the plasma protein transthyretin. So far, high resolution structures of only three amyloidogenic variants (Met30, Ser84, Ile122) and one non-amyloidogenic variant (Thr109) have been reported complemented by X-ray fiber diffraction studies and image reconstruction from electron micrographs of amyloid fibrils. To investigate the role of structural factors in this disease, we extended our studies to other transthyretin variants. We report crystallization and structural investigations of three amyloidogenic (Arg10, Ala60, Tyr77) and two non-amyloidogenic variants (Ser6, Met119). The similarity of these structures to normal transthyretin does not give direct clues to the fibril forming process. Since transthyretin amyloid fibrils contain a major fragment starting at position 49, besides the intact molecule, we calculated the solvent accessibility of residue 48. Indeed, all amyloidogenic variants show an increased main chain solvent exposure when compared to normal transthyretin and non-amyloidogenic variants, which can be postulated to result in increased susceptibility to proteolysis. After limited proteolysis, dimers are incapable of reassociation to native tetramers. We present a model for amyloid fibril formation based on formation of fibrils from N-terminal truncated dimers as building blocks.

Literature references that cite this PDB file's key reference

PubMed id

Reference

19602727

L.Cendron, A.Trovato, F.Seno, C.Folli, B.Alfieri, G.Zanotti, and R.Berni (2009).
Amyloidogenic potential of transthyretin variants: insights from structural and computational analyses.

J Biol Chem, 284, 25832-25841.

PDB codes:

3djr 3djs 3djt 3djz 3dk0 3dk2

18474516

F.Lavatelli, D.H.Perlman, B.Spencer, T.Prokaeva, M.E.McComb, R.Théberge, L.H.Connors, V.Bellotti, D.C.Seldin, G.Merlini, M.Skinner, and C.E.Costello (2008).
Amyloidogenic and associated proteins in systemic amyloidosis proteome of adipose tissue.

Mol Cell Proteomics, 7, 1570-1583.

19021760

G.Zanotti, C.Folli, L.Cendron, B.Alfieri, S.K.Nishida, F.Gliubich, N.Pasquato, A.Negro, and R.Berni (2008).
Structural and mutational analyses of protein-protein interactions between transthyretin and retinol-binding protein.

FEBS J, 275, 5841-5854.

PDB codes:

3bsz 3bt0 3cxf

18162431

J.G.Ghosh, S.A.Houck, and J.I.Clark (2008).
Interactive sequences in the molecular chaperone, human alphaB crystallin modulate the fibrillation of amyloidogenic proteins.

Int J Biochem Cell Biol, 40, 954-967.

18214980

M.Mizuguchi, A.Hayashi, M.Takeuchi, M.Dobashi, Y.Mori, H.Shinoda, T.Aizawa, M.Demura, and K.Kawano (2008).
Unfolding and aggregation of transthyretin by the truncation of 50 N-terminal amino acids.

Proteins, 72, 261-269.

17381508

X.Hou, M.I.Aguilar, and D.H.Small (2007).
Transthyretin and familial amyloidotic polyneuropathy. Recent progress in understanding the molecular mechanism of neurodegeneration.

FEBS J, 274, 1637-1650.

16169975

M.Calamai, F.Chiti, and C.M.Dobson (2005).
Amyloid fibril formation can proceed from different conformations of a partially unfolded protein.

Biophys J, 89, 4201-4210.

15033978

M.A.Liz, C.J.Faro, M.J.Saraiva, and M.M.Sousa (2004).
Transthyretin, a new cryptic protease.

J Biol Chem, 279, 21431-21438.

12668424

G.Moraitakis, and J.M.Goodfellow (2003).
Simulations of human lysozyme: probing the conformations triggering amyloidosis.

Biophys J, 84, 2149-2158.

14690414

Y.Shinohara, M.Mizuguchi, K.Matsubara, M.Takeuchi, A.Matsuura, T.Aoki, K.Igarashi, H.Nagadome, Y.Terada, and K.Kawano (2003).
Biophysical analyses of the transthyretin variants, Tyr114His and Tyr116Ser, associated with familial amyloidotic polyneuropathy.

Biochemistry, 42, 15053-15060.

10077645

G.Goldsteins, H.Persson, K.Andersson, A.Olofsson, I.Dacklin, A.Edvinsson, M.J.Saraiva, and E.Lundgren (1999).
Exposure of cryptic epitopes on transthyretin only in amyloid and in amyloidogenic mutants.

Proc Natl Acad Sci U S A, 96, 3108-3113.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.