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BEACH proteins

The BEACH (Beige and Chediak Higashi) domain is a highly conserved, ~280 residue domain found in nine human proteins, referred to as BEACH domain containing proteins (BDCPs). Most BDCPs are large proteins containing a PH-domain preceding the BEACH-domain, followed by several consecutive WD40-repeats. Several studies have identified mutations in individual BDCPs linked to various human diseases, but the precise function of the BEACH domain and most BDCPs are yet to be revealed.

Illustration: Peter Holland

About the project

We have previously identified the BDCP ALFY (Autophagy-linked FYVE protein) as being important for selective autophagy of aggregate-prone proteins associated with Huntington’s and Parkinson’s disease. ALFY interacts with the ubiquitin-binding autophagy receptor p62 and links ubiquitinated proteins to the core autophagic machinery through its interactions with ATG5 and PI3P. This project aims to further characterize of the localization and cellular function of all BDCPs. Such knowledge will provide important insight to the pathology in a widespread selection of diseases and may lead to identification of potential diagnostic markers or targets for therapy. An approach combining state-of-the-art genomics, imaging and proteomics technologies with clinically relevant systems and cell biological models, will be used to address these questions.

Outcomes/Recent findings

  • ALFY and p62 interacts with the mitochondria proteins NIPSNAP1 and -2 to facilitate mitophagy (PMID: 30982665)
  • ALFY is critical for the granulocytic differentiation of AML cells (PMID: 29021535)
  • Alfy/WDFY3 is required for establishing neuronal connectivity in the mammalian brain. PMID 27648578
  • Structural determinants in GABARAP required for the selective binding and recruitment of ALFY to LC3B-positive structures (PMID: 24668264)
  • LYST affects lysosome size and quantity, but not trafficking or degradation through autophagy or endocytosis (25216107)
  • The selective macroautophagic degradation of aggregated proteins requires the PI3P-binding protein Alfy. (PMID  20417604)

Funding

The University of Oslo, The Research Council of Norway

Collaborations

  • Ai Yamamoto, Columbia University, New Work
  • Kim Finley, San Diego State University
  • Terje Johansen, University of Tromsø
Published Apr. 11, 2013 11:14 AM - Last modified Dec. 9, 2019 1:04 PM

Contact

Project leader

Anne Simonsen

Department of Molecular Medicine
Domus Medica
Gaustad
Sognsvannsveien 9
0372 Oslo