title: Structural basis for recognition of acidic-cluster dileucine sequence by GGA1.
abstract: 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.
authors.affiliation: Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki 305-0801, Japan.
authors.forename: Tomoo
authors.initials: T
authors.lastname: Shiba
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takatsu
authors.forename: Terukazu
authors.initials: T
authors.lastname: Nogi
authors.forename: Naohiro
authors.initials: N
authors.lastname: Matsugaki
authors.forename: Masato
authors.initials: M
authors.lastname: Kawasaki
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Igarashi
authors.forename: Mamoru
authors.initials: M
authors.lastname: Suzuki
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Kato
authors.forename: Thomas
authors.initials: T
authors.lastname: Earnest
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Nakayama
authors.forename: Soichi
authors.initials: S
authors.lastname: Wakatsuki
mesh_terms: D020727:ADP-Ribosylation Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D033942:Adaptor Proteins, Vesicular Transport; D000595:Amino Acid Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004926:Escherichia coli; D006863:Hydrogen-Ion Concentration; D007930:Leucine / Q000737:chemistry / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D017527:Receptor, IGF Type 2 / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D013329:Structure-Activity Relationship; D020798:Two-Hybrid System Techniques; D000099183:Sortilin
chemical_list: D020727:ADP-Ribosylation Factors; D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D007930:Leucine; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D017527:Receptor, IGF Type 2; D000099183:Sortilin; C407306:GGA adaptor proteins