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Pleckstrin homology-like domain of Regulatory Particle Non-ATPase 13 Targeted protein degradation is performed to a great extent by the ubiquitin-proteasome pathway, in which substrate proteins are marked by covalently attached ubiquitin chains that mediate recognition by the proteasome. Rpn13(also called ADRM1/ARM1) is one of the two major ubiquitin receptors of the proteasome, the other being S5a/Rpn10 which is not essential for ubiquitin-mediated protein degradation in budding yeast2. S5a has two ubiquitin interacting motifs (UIMs) that bind simultaneously to ubiquitin moieties to increase affinity while Rpn13 binds ubiquitin with a single, high affinity surface within its N-terminal PH domain. Rpn13 also binds and activates deubiquitinating enzyme Uch37, one of the proteasome's three deubiquitinating enzymes. Recently it was discovered that the ubiquitin-binding domain (BD) and Uch37 BD of human (h) Rpn13 pack against each other when it is not incorporated into the proteasome reducing hRpn13's affinity for ubiquitin. However when hRpn13 binds to hRpn2/S1 this abrogates its interdomain interactions, thus activating hRpn13 for ubiquitin binding. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes. |
Jiyao W et al.(2023). "The conserved domain database in 2023.",