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Mutually exclusive binding of PP1 and RNA to AKAP149 affects the mitochondrial network

Marie Rogne1, Anne Jorunn Stokka, Kjetil Taskén

  • 11Institute of Basic Medical Sciences, Department of Biochemistry, University of Oslo, Post Box 1112, Blindern, 0317 Oslo, Norway.

Human Molecular Genetics
|December 17, 2008
PubMed

Insights

A-kinase-anchoring protein 149 (AKAP149) tethers protein kinases and phosphatases to cellular membranes. Its RNA-binding function is crucial for maintaining mitochondrial network structure, with disruptions leading to collapse.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Neuroscience

Background:

  • A-kinase-anchoring protein 149 (AKAP149) is a key scaffolding protein regulating protein phosphorylation at the mitochondria and endoplasmic reticulum/nuclear envelope.
  • AKAP149 possesses an RNA-binding K homology (KH) domain, mutations in which are linked to neurodegenerative diseases in other proteins.

Purpose of the Study:

  • To investigate the mechanism of protein phosphatase 1 (PP1) binding to AKAP149.
  • To elucidate the interplay between PP1 binding, RNA binding, and phosphorylation within the AKAP149 KH domain.
  • To determine the role of AKAP149's RNA-binding function in mitochondrial morphology and distribution.

Main Methods:

  • Biochemical assays to identify the PP1 binding site on AKAP149.
  • Mutagenesis studies to assess the impact of altered RNA-binding or PP1-binding motifs.
  • Cellular imaging techniques to observe mitochondrial network structure in response to AKAP149 mutants.

Main Results:

  • PP1 binds to AKAP149 via a conserved RVXF motif within the KH domain.
  • PP1 binding and RNA binding to the KH domain are mutually exclusive and regulated by phosphorylation.
  • AKAP149 mutants deficient in RNA binding cause mitochondrial network collapse, highlighting the importance of RNA tethering for mitochondrial distribution.

Conclusions:

  • AKAP149's KH domain acts as a regulatory hub for both protein phosphatase 1 interaction and RNA binding.
  • Phosphorylation-dependent control of this hub dictates the functional state of AKAP149.
  • AKAP149-mediated RNA tethering to mitochondria is essential for maintaining mitochondrial network integrity.

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