Pleckstrin homology-like domain or GLUE (GRAM-like ubiquitin-binding in Eap45) domain of Vps36
ESCRT complexes form the main machinery driving protein sorting from endosomes to lysosomes. Yeast/human ESCRT-I consists of Vps23/Tsg101, Vps28/Vps28, and Vps37/Vps37 homolog. Yeast/human ESCRT-II is composed of Vps25/EAP20, Vps22/EAP30, and Vps36/EAP45. Yeast ESCRT-III consists Vps2, Vps20, Vps24, and Snf7 subunits. In contrast, there are three human paralogs of Snf7 (hSnf7-1/CHMP4A, hSnf7-2/CHMP4B, and hSnf7-3/CHMP4C) and two paralogs of Vps2 (CHMP2A and CHMP2B). Yeast ESCRT-I links directly to ESCRT-II, through a tight interaction of Vps28 (ESCRT-I) with the yeast-specific zinc-finger insertion within the GLUE domain of Vps36. The Vps36 subunit (ESCRT-II) binds ubiquitin using one of its two NZF zinc fingers in its N-terminal region. Human Vps36, EAP45, also binds ubiquitin despite having no NZF domain. Instead, mammalian ESCRT-II interacts with Ub through the Eap45 GLUE domain itself. The yeast Vps36 GLUE has a complete PH domain, wherease Eap45 GLUE only has a PH-like fold since it lacks the secondary structure element corresponding to the 4 strand. ESCRT-II also interacts with ESCRT-III via a Vps25(EAP20)/Vps20(CHMP6) interaction. Structure 2CAY is missing this insertion that contains 2 NZF zinc fingers. It is a split PH domain, with a noncanonical lipid binding pocket that binds PI(3)P. The interactions of ESCRT-II GLUE domain with membranes, ESCRT-I, and ubiquitin are critical for ubiquitinated cargo progression from early to late endosomes. 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.",