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A new kid in the folding funnel: Molecular chaperone activities of the BRICHOS domain

Axel Leppert1,2, Helen Poska3, Michael Landreh2

  • 1Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.

Protein Science : a Publication of the Protein Society
|April 25, 2023
PubMed

Insights

The BRICHOS protein superfamily, implicated in diseases like dementia and cancer, features a domain that chaperones proteins during biosynthesis. This review explores their diverse molecular chaperone functions and therapeutic potential for protein aggregation disorders.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Protein Folding

Background:

  • The BRICHOS protein superfamily is linked to various human diseases, including respiratory distress, COVID-19, dementia, and cancer.
  • These proteins possess a BRICHOS domain and an aggregation-prone region, with the domain proposed to chaperone substrates during biosynthesis.
  • BRICHOS domains modulate amyloid-forming substrate aggregation pathways, with varying capacities to maintain protein folding competence.

Purpose of the Study:

  • To provide an overview of the BRICHOS protein family.
  • To explore the diverse molecular chaperone-like functions of BRICHOS domains in relation to their structure and conformational plasticity.
  • To discuss the physiological implications of these chaperone functions and their potential therapeutic use.

Main Methods:

  • Literature review and analysis of existing evidence on BRICHOS proteins.
  • Examination of structure-function relationships of BRICHOS domains.
  • Exploration of potential therapeutic applications based on molecular chaperone activity.

Main Results:

  • BRICHOS domains exhibit diverse molecular chaperone activities, influencing aggregation pathways of various substrates.
  • The quaternary structure and surface motifs of BRICHOS domains dictate their ability to interfere with substrate aggregation.
  • The conformational plasticity of BRICHOS domains is crucial for their chaperone function.

Conclusions:

  • BRICHOS domains possess versatile molecular chaperone functions critical for protein homeostasis.
  • Their structure and plasticity determine their efficacy in modulating protein aggregation.
  • BRICHOS domains hold promise as potential therapeutic agents for protein aggregation disorders, including potential blood-brain barrier permeability.

Keywords:
Alzheimer disease treatmentamyloidblood-brain barriermolecular chaperoneprotein misfolding

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