title: The Chediak-Higashi protein interacts with SNARE complex and signal transduction proteins.
abstract: BACKGROUND
  Chediak-Higashi syndrome (CHS) is an inherited immunodeficiency disease characterized by giant lysosomes and impaired leukocyte degranulation. CHS results from mutations in the lysosomal trafficking regulator (LYST) gene, which encodes a 425-kD cytoplasmic protein of unknown function. The goal of this study was to identify proteins that interact with LYST as a first step in understanding how LYST modulates lysosomal exocytosis.
  
  
  METHODS
  Fourteen cDNA fragments, covering the entire coding domain of LYST, were used as baits to screen five human cDNA libraries by a yeast two-hybrid method, modified to allow screening in the activation and the binding domain, three selectable markers, and more stringent confirmation procedures. Five of the interactions were confirmed by an in vitro binding assay.
  
  
  RESULTS
  Twenty-one proteins that interact with LYST were identified in yeast two-hybrid screens. Four interactions, confirmed directly, were with proteins important in vesicular transport and signal transduction (the SNARE-complex protein HRS, 14-3-3, and casein kinase II).
  
  
  CONCLUSIONS
  On the basis of protein interactions, LYST appears to function as an adapter protein that may juxtapose proteins that mediate intracellular membrane fusion reactions. The pathologic manifestations observed in CHS patients and in mice with the homologous mutation beige suggest that understanding the role of LYST may be relevant to the treatment of not only CHS but also of diseases such as asthma, urticaria, and lupus, as well as to the molecular dissection of the CHS-associated cancer predisposition.
authors: CuraGen Corporation, New Haven, CT 06511, USA. velizart@molecularstaging.com
authors: Velizar T
authors: VT
authors: Tchernev
authors: Traci A
authors: TA
authors: Mansfield
authors: Loic
authors: L
authors: Giot
authors: A Madan
authors: AM
authors: Kumar
authors: Krishnan
authors: K
authors: Nandabalan
authors: Ying
authors: Y
authors: Li
authors: Vishnu S
authors: VS
authors: Mishra
authors: John C
authors: JC
authors: Detter
authors: Jonathan M
authors: JM
authors: Rothberg
authors: Margaret R
authors: MR
authors: Wallace
authors: Frederick S
authors: FS
authors: Southwick
authors: Stephen F
authors: SF
authors: Kingsmore
mesh_terms: D048948:14-3-3 Proteins; D000818:Animals; D047390:Casein Kinase II; D018076:DNA, Complementary / Q000235:genetics; D056827:Endosomal Sorting Complexes Required for Transport; D005089:Exocytosis / Q000502:physiology; D015723:Gene Library; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000378:metabolism; D046911:Macromolecular Substances; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D025941:Protein Interaction Mapping; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D019210:Troponin I / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*; D033921:Vesicular Transport Proteins
chemical_list: D048948:14-3-3 Proteins; D018076:DNA, Complementary; D056827:Endosomal Sorting Complexes Required for Transport; D047908:Intracellular Signaling Peptides and Proteins; C102161:LYST protein, human; C491133:Lyst protein, mouse; D046911:Macromolecular Substances; D010446:Peptide Fragments; D010750:Phosphoproteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; D019210:Troponin I; D033921:Vesicular Transport Proteins; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; D014446:Tyrosine 3-Monooxygenase; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases