How does ubiquitination achieve its remarkable selectivity and efficiency? This review explores the mechanisms underlying ubiquitination, a crucial process in eukaryotic cells that regulates diverse cellular functions. The high efficiency and exquisite selectivity of ubiquitination reactions reflect the properties of enzymes known as ubiquitin-protein ligases or E3s. An E3 recognizes its substrates based on the presence of a specific ubiquitination signal, and catalyzes the formation of an isopeptide bond between a substrate (or ubiquitin) lysine residue and the C terminus of ubiquitin. The review examines how all known E3s use one of two catalytic domains—a HECT domain or a RING finger—and discusses recent crystal structures that provide detailed views of an active site of each type. Recent findings reveal that all known E3s utilize one of just two catalytic domains—a HECT domain or a RING finger—and crystal structures have provided the first detailed views of an active site of each type. The new findings shed light on many aspects of E3 structure, function, and mechanism, but also emphasize that key features of E3 catalysis remain to be elucidated. By highlighting the molecular basis of E3 specificity and catalysis, this paper offers insights into fundamental regulatory mechanisms within cells.
Published in Annual Review of Biochemistry, this review aligns with the journal’s focus on fundamental biochemical processes. By exploring the mechanisms of ubiquitination, the paper engages with topics in enzymology, protein structure, and cell signaling. This comprehensive overview contributes significantly to the understanding of cellular regulation.
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