Structural Analysis of the UBA Domain of X-linked Inhibitor of Apoptosis Protein Reveals Different Surfaces for Ubiquitin-Binding and Self-Association

Autor: Hong-Yu Hu, Si-Tao Yin, Benjamin Chun Yu Wong, Man-Kit Tse, Kong-Hung Sze, Yinhua Yang, Bing Zou, Sin Kam Hui
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Macromolecular Assemblies
Models
Molecular
Magnetic Resonance Spectroscopy
Ubiquitin binding
Plasma protein binding
Biochemistry
Protein structure
Ubiquitin
Protein Interaction Mapping
X-Linked Inhibitor of Apoptosis Protein - chemistry - metabolism
Macromolecular Structure Analysis
Biomacromolecule-Ligand Interactions
Polyubiquitin
Lysine - metabolism
Multidisciplinary
biology
Recombinant Proteins
XIAP
Cell biology
Enzymes
Solutions
Medicine
Research Article
Protein Binding
Protein Structure
Surface Properties
Science
Protein domain
Molecular Sequence Data
Biophysics
X-Linked Inhibitor of Apoptosis Protein
Inhibitor of apoptosis
Enzyme Regulation
Structure-Activity Relationship
Humans
Amino Acid Sequence
Binding site
Protein Interactions
Biology
Ubiquitins
Binding Sites
Lysine
Proteins
Computational Biology
Molecular biology
Regulatory Proteins
Protein Structure
Tertiary
Ubiquitin - metabolism
Enzyme Structure
biology.protein
Globular Proteins
Protein Multimerization
Sequence Alignment
Zdroj: PLoS ONE
PLoS ONE, Vol 6, Iss 12, p e28511 (2011)
ISSN: 1932-6203
Popis: BACKGROUND: Inhibitor of apoptosis proteins (IAPs) belong to a pivotal antiapoptotic protein family that plays a crucial role in tumorigenesis, cancer progression, chemoresistance and poor patient-survival. X-linked inhibitor of apoptosis protein (XIAP) is a prominent member of IAPs attracting intense research because it has been demonstrated to be a physiological inhibitor of caspases and apoptosis. Recently, an evolutionarily conserved ubiquitin-associated (UBA) domain was identified in XIAP and a number of RING domain-bearing IAPs. This has placed the IAPs in the group of ubiquitin binding proteins. Here, we explore the three-dimensional structure of the XIAP UBA domain (XIAP-UBA) and how it interacts with mono-ubiquitin and diubiquitin conjugates. PRINCIPAL FINDINGS: The solution structure of the XIAP-UBA domain was determined by NMR spectroscopy. XIAP-UBA adopts a typical UBA domain fold of three tightly packed alpha-helices but with an additional N-terminal 3(10) helix. The XIAP-UBA binds mono-ubiquitin as well as Lys48-linked and linear-linked diubiquitins at low-micromolar affinities. NMR analysis of the XIAP-UBA-ubiquitin interaction reveals that it involves the classical hydrophobic patches surrounding Ile44 of ubiquitin and the conserved MGF/LV motif surfaces on XIAP-UBA. Furthermore, dimerization of XIAP-UBA was observed. Mapping of the self-association surface of XIAP-UBA reveals that the dimerization interface is formed by residues in the N-terminal 3(10) helix, helix alpha1 and helix alpha2, separate from the ubiquitin-binding surface. CONCLUSION: Our results provide the first structural information of XIAP-UBA and map its interaction with mono-ubiquitin, Lys48-linked and linear-linked diubiquitins. The notion that XIAP-UBA uses different surfaces for ubiquitin-binding and self-association provides a plausible model to explain the reported selectivity of XIAP in binding polyubiquitin chains with different linkages.
published_or_final_version
Databáze: OpenAIRE
Externí odkaz: