Detecting hidden sequence propensity for amyloid fibril formation

Sukjoon Yoon, William Welsh

Research output: Contribution to journalArticle

84 Citations (Scopus)

Abstract

The preponderance of evidence implicates protein misfolding in many unrelated human diseases. In all cases, normal correctly folded proteins transform from their proper native structure into an abnormal β-rich structure known as amyloid fibril. Here we introduce a computational algorithm to detect nonnative (hidden) sequence propensity for amyloid fibril formation. Analyzing sequence-structure relationships in terms of tertiary contact (TC), we find that the hidden β-strand propensity of a query local sequence can be quantitatively estimated from the secondary structure preferences of template sequences of known secondary structure found in regions of high TC. The present method correctly pinpoints the minimal peptide fragment shown experimentally as the likely local mediator of amyloid fibril formation in β-amyloid peptide, islet amyloid polypeptide (hIAPP), α-synuclein, and human acetylcholinesterase (AChE). It also found previously unrecognized β-strand propensities in the prototypical helical protein myoglobin that has been reported as amyloidogenic. Analysis of 2358 nonhomologous protein domains provides compelling evidence that most proteins contain sequences with significant hidden β-strand propensity. The present method may find utility in many medically relevant applications, such as the engineering of protein sequences and the discovery of therapeutic agents that specifically target these sequences for the prevention and treatment of amyloid diseases.

Original languageEnglish (US)
Pages (from-to)2149-2160
Number of pages12
JournalProtein Science
Volume13
Issue number8
DOIs
StatePublished - Aug 1 2004

Fingerprint

Amyloid
Proteins
Synucleins
Islet Amyloid Polypeptide
Protein Engineering
Peptide Fragments
Myoglobin
Acetylcholinesterase
Peptides
Therapeutics

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology

Keywords

  • Amyloid fibril
  • Hidden β-strand propensity
  • HβP, SCOP
  • Secondary structure
  • Tertiary contacts

Cite this

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Detecting hidden sequence propensity for amyloid fibril formation. / Yoon, Sukjoon; Welsh, William.

In: Protein Science, Vol. 13, No. 8, 01.08.2004, p. 2149-2160.

Research output: Contribution to journalArticle

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