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Structural basis for recognition of acidic-cluster dileucine sequence by GGA1.

GGAs (Golgi-localizing, gamma-adaptin ear homology domain, ARF-interacting proteins) are critical for the transport of soluble proteins from the trans-Golgi network (TGN) to endosomes/lysosomes by means of interactions with TGN-sorting receptors, ADP-ribosylation factor (ARF), and clathrin. The amino-terminal VHS domains of GGAs form complexes with the cytoplasmic domains of sorting receptors by recognizing acidic-cluster dileucine (ACLL) sequences. Here we report the X-ray structure of the GGA1 VHS domain alone, and in complex with the carboxy-terminal peptide of cation-independent mannose 6-phosphate receptor containing an ACLL sequence. The VHS domain forms a super helix with eight alpha-helices, similar to the VHS domains of TOM1 and Hrs. Unidirectional movements of helices alpha6 and alpha8, and some of their side chains, create a set of electrostatic and hydrophobic interactions for correct recognition of the ACLL peptide. This recognition mechanism provides the basis for regulation of protein transport from the TGN to endosomes/lysosomes, which is shared by sortilin and low-density lipoprotein receptor-related protein.

Pubmed ID: 11859376

Authors

  • Shiba T
  • Takatsu H
  • Nogi T
  • Matsugaki N
  • Kawasaki M
  • Igarashi N
  • Suzuki M
  • Kato R
  • Earnest T
  • Nakayama K
  • Wakatsuki S

Journal

Nature

Publication Data

February 21, 2002

Associated Grants

None

Mesh Terms

  • ADP-Ribosylation Factors
  • Adaptor Proteins, Vesicular Transport
  • Amino Acid Sequence
  • Binding Sites
  • Carrier Proteins
  • Cloning, Molecular
  • Crystallography, X-Ray
  • Escherichia coli
  • Hydrogen-Ion Concentration
  • Leucine
  • Membrane Glycoproteins
  • Models, Molecular
  • Molecular Sequence Data
  • Nerve Tissue Proteins
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Protein Transport
  • Receptor, IGF Type 2
  • Structure-Activity Relationship
  • Two-Hybrid System Techniques