Pharmacologic rescue of conformationally-defective proteins: Implications for the treatment of human disease

Alfredo Ulloa-Aguirre, Jo Ann Janovick, Shaun P Brothers, P. Michael Conn

Research output: Contribution to journalArticle

216 Citations (Scopus)

Abstract

The process of quality in the endoplasmic reticulum involves a variety of mechanisms which ensure that only correctly folded proteins enter the secretory pathway. Among these are conformation-screening mechanisms performed by molecular chaperones that assist in protein folding and prevent non-native (or misfolded) proteins from interacting with other misfolded proteins. Chaperones play a central role in the triage of newly formed proteins prior to their entry into the secretion, retention, and degradation pathways. Despite this stringent quality control mechanism, gain- or loss-of-function mutations that affect protein folding in the endoplasmic: reticulum can manifest themselves as profound effects on the health of an organism. Understanding the molecular, cellular, and energetic mechanisms of protein routing couild prevent or correct the structural abnormalities associated with disease-causing misfolded proteins. Rescue of misfolded, "trafficking-defective", but otherwise functional, proteins is achieved by a variety of physical, chemical, genetic, and pharmacological approaches. Pharmacologic chaperones (or "pharmacoperones") are template molecules that may potentially arrest or reverse diseases by inducing mutant proteins to adopt native-type-like conformations instead of improperly folded ones. Such restructuring leads to a normal pattern of cellular localization and function. This review focuses on protein misfolding and misrouting related to various disease states and describes promising approaches to overcoming such defects. Special attention is paid to the gonadotropin-releasing hormone receptor, since there is a great deal of information about this receptor, which has recently emerged as a particularly instructive model.

Original languageEnglish
Pages (from-to)821-837
Number of pages17
JournalTraffic
Volume5
Issue number11
DOIs
StatePublished - Nov 1 2004
Externally publishedYes

Fingerprint

Proteins
Protein folding
Protein Folding
Endoplasmic Reticulum
Proteostasis Deficiencies
Conformations
LHRH Receptors
Molecular Chaperones
Triage
Secretory Pathway
Mutant Proteins
Quality Control
Quality control
Screening
Pharmacology
Health
Mutation
Degradation
Defects
Molecules

Keywords

  • Conformational disease
  • Gonadotropin-releasing hormone receptor
  • Pharmacological chaperone
  • Pharmacoperone

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Structural Biology
  • Molecular Biology
  • Genetics

Cite this

Pharmacologic rescue of conformationally-defective proteins : Implications for the treatment of human disease. / Ulloa-Aguirre, Alfredo; Janovick, Jo Ann; Brothers, Shaun P; Conn, P. Michael.

In: Traffic, Vol. 5, No. 11, 01.11.2004, p. 821-837.

Research output: Contribution to journalArticle

Ulloa-Aguirre, Alfredo ; Janovick, Jo Ann ; Brothers, Shaun P ; Conn, P. Michael. / Pharmacologic rescue of conformationally-defective proteins : Implications for the treatment of human disease. In: Traffic. 2004 ; Vol. 5, No. 11. pp. 821-837.
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