Ubiquitylated proteins are degraded by the 26 S protease, an enzyme complex that contains 30 or more unique subunits. One of these proteins, subunit 5a (S5a), has been shown to bind ubiquitin-lysozyme conjugates and free polyubiquitin chains. Using deletional analysis, we have identified in the carboxyl-terminal half of human S5a, two independent polyubiquitin binding sites whose sequences are highly conserved among higher eukaryotic S5a homologs. The sites are approximately 30-amino acids long and are separated by 50 intervening residues. When expressed as small fragments or when present in full-length S5a molecules, the sites differ at least 10-fold in their apparent affinity for polyubiquitin chains. Each binding site contains 5 hydrophobic residues that form an alternating pattern of large and small side chains, e.g. Leu-Ala-Leu-Ala-Leu, and this pattern is essential for binding ubiquitin chains. Based on the importance of the alternating hydrophobic residues in the binding sites and previous studies showing that a hydrophobic patch on the surface of ubiquitin is essential for proteolytic targeting, we propose a model for molecular recognition of polyubiquitin chains by S5a.
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