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Identification of binding partners that facilitate membrane-type 5 matrix metalloproteinase (MT5-MMP) processing of

Hongjie Wang1, Madepalli K Lakshmana2, Gregg B Fields1

  • 1Department of Chemistry & Biochemistry, Institute for Human Health & Disease Intervention (I-HEALTH), Florida Atlantic University, Jupiter, Florida, USA.

Journal of Cellular Physiology
|February 12, 2024
PubMed

Insights

Alzheimer's disease involves amyloid beta plaques. This study shows membrane-type 5 matrix metalloproteinase (MT5-MMP) interacts with amyloid precursor protein (APP) in various cell locations, increasing amyloid production. Specific binding partners enhance this effect.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Alzheimer's disease (AD) is characterized by amyloid beta (Aβ) plaques.
  • Amyloid precursor protein (APP) processing and fragments like Aβ are implicated in AD pathogenesis.
  • The APPη pathway, mediated by membrane-type 5 matrix metalloproteinase (MT5-MMP), is a key factor in AD.

Purpose of the Study:

  • To determine the intracellular localization of APPη cleavage by MT5-MMP.
  • To identify MT5-MMP protein partners that influence APP processing.
  • To understand the role of MT5-MMP in Alzheimer's disease pathogenesis.

Main Methods:

  • Localization studies of MT5-MMP in CHO cells expressing human APP751.
  • Construction and analysis of MT5-MMP fusion proteins targeted to various organelles.
  • Yeast two-hybrid screening using the C-terminal domain of MT5-MMP to identify binding partners.

Main Results:

  • MT5-MMP was found in the nucleus, cytosol, and cytosolic granules.
  • Targeting MT5-MMP to the endosome, Golgi, plasma membrane, or mitochondria increased soluble APPη (sAPPη).
  • Binding partners including N4BP2L1, EIG121, BIN1, and TMX3 significantly enhanced sAPPη production upon binding to MT5-MMP.

Conclusions:

  • MT5-MMP acts on APP in multiple cellular compartments.
  • The effect of MT5-MMP on APP is facilitated by specific binding partners.
  • This interaction represents a significant pathway in Alzheimer's disease development.
Keywords:
Alzheimer's diseaseamyloid precursor proteinintracellular proteolysismembrane‐type 5 matrix metalloproteinasesecretase

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