Huntingtin-interacting protein 1 (HIP1) belongs to the Sla2 family. HIP1 was first identified due to its interaction with huntingtin (htt), a protein that when mutated is involved in the genetic neurodegenerative disorder Huntington's disease []. Later, HIP1 was found to play a role in trafficking and is linked to cancers []. HIP1 depends on clathrin for its membrane localisation and plays a role in pits maturation and formation of the coated vesicle []. Besides endocytosis, HIP1 is also involved in cellular processes such as tumorigenesis [], transcription regulation []and cell death [].The Sla2 family, also known as Sla2p/HIP1/HIP1R family, including Sla2p from budding yeasts [], End4 from fission yeasts [], Huntingtin-interacting protein 1 (HIP1) and HIP1-related (HIP1R) from humans and mice []. They are adaptor proteins thatlink actin to clathrin and endocytosis in the clathrin-mediated endocytosis (CME) pathway. They contain the ENTH and ANTH (E/ANTH) domain that binds both inositol phospholipids and proteins that contribute to the nucleation and formation of clathrin coats on membranes []. They also contain an I/LWEQ (talin-like) domain, which is an actin-binding domain found in proteins that serve as linkers between the actin cytoskeleton and cellular compartments []. The talin-like domains of Sla2p and HIP1R have been shown to bind F-actin (filamentous actin), however, the same level of actin binding has not been observed with HIP1 []. The central domain of the Sla2p/HIP1/HIP1R proteins contains a coiled-coil domain and several consensus sequences enabling protein-protein interactions []. Yeast Sla2p has been extensively studied: Sla2p arrives at existing endocytic patches with a ~25 seconds delay relative to clathrin and dissociates simultaneously with clathrin upon recruitment of actin-related proteins [, ]. It serves as a bridge, connecting the endocytic patch to the cortical actin cytoskeleton [].
This entry represents the coiled-coil region of Huntingtin-interacting protein 1 (HIP1). It carries a highly conserved HADLLRKN sequence motif at its N terminus which effects the binding of HIP1R to clathrin light-chain EED regulatory site. This binding then stimulates clathrin lattice assembly. HIP1 is an obligate binding partner for Huntingtin, and loss of this interaction triggers the cascade of events that results in the apoptosis of neuronal cells and the onset of Huntington's disease []. Clathrin light-chain binds to a flexible coiled-coil domain in HIP1 and induces a compact state that is refractory to actin binding [].
The I/LWEQ domain is a ~250-residue actin-binding module that is found in theC termini of functionally diverse proteins from yeast to mammals. The I/LWEQdomain contains four conserved blocks and has been named after the conservedinitial residues of blocks 1-4. The I/LWEQ domain is generally found near theC terminus and in association with other domains, such as FERM or ENTH. The I/LWEQ domain has been shown to bind to F-actin and to bundle actin filaments [, , ].The I/LWEQ domain contains a proteolysis resistant-core that has an all-α-helical structure composed of five long down-up-down-up-down antiparallelhelices connected by short loops and one short connecting alpha helix arranged in a progressive topology. The proteolysis-resistant core isfollowed by a C-terminal latch region that adopts an α-helicalconformation. The latch region can mediate oligomerization of I/LWEQ domains,possibly as dimers, and this seems to enhance the F-actin-binding ability ofthe proteolysis-resistant core [].It's worth noting that the I/LWEQ domain has also been called the talin-HIP1/R/Slap2p actin- tethering C-terminal homology (THATCH) domain (HIP1/R/Slap2p denotes similarity of Slap2p to HIP1 and HIP1R) [].
The I/LWEQ domain is a ~250-residue actin-binding module that is found in theC termini of functionally diverse proteins from yeast to mammals. The I/LWEQdomain contains four conserved blocks and has been named after the conservedinitial residues of blocks 1-4. The I/LWEQ domain is generally found near theC terminus and in association with other domains, such as FERM or ENTH. The I/LWEQ domain has been shown to bind to F-actin and to bundle actin filaments [, , ].The I/LWEQ domain contains a proteolysis resistant-core that has an all-α-helical structure composed of five long down-up-down-up-down antiparallelhelices connected by short loops and one short connecting alpha helix arranged in a progressive topology. The proteolysis-resistant core isfollowed by a C-terminal latch region that adopts an α-helicalconformation. The latch region can mediate oligomerization of I/LWEQ domains,possibly as dimers, and this seems to enhance the F-actin-binding ability ofthe proteolysis-resistant core [].It's worth noting that the I/LWEQ domain has also been called the talin-HIP1/R/Slap2p actin- tethering C-terminal homology (THATCH) domain (HIP1/R/Slap2p denotes similarity of Slap2p to HIP1 and HIP1R) [].
Huntingtin-interacting protein 1-related protein (HIP1R, also known as HIP-12) belongs to the Sla2 family. HIP1R is the only known mammalian relative of huntingtin-interacting protein 1 (HIP1) []. HIP1R may have a role in actin regulation during endocytosis and is shown to promote clathrin assembly. It may also be involved in the apoptotic pathway through its interaction with a member of the Bcl-2 pro-apoptotic family [].The Sla2 family, also known as Sla2p/HIP1/HIP1R family, including Sla2p from budding yeasts [], End4 from fission yeasts [], Huntingtin-interacting protein 1 (HIP1) and HIP1-related (HIP1R) from humans and mice []. They are adaptor proteins that link actin to clathrin and endocytosis in the clathrin-mediated endocytosis (CME) pathway. They contain the ENTH and ANTH (E/ANTH) domain that binds both inositol phospholipids and proteins that contribute to the nucleation and formation of clathrin coats on membranes []. They also contain an I/LWEQ (talin-like) domain, which is an actin-binding domain found in proteins that serve as linkers between the actin cytoskeleton and cellular compartments []. The talin-like domains of Sla2p and HIP1R have been shown to bind F-actin (filamentous actin), however, the same level of actin binding has not been observed with HIP1 []. The central domain of the Sla2p/HIP1/HIP1R proteins contains a coiled-coil domain and several consensus sequences enabling protein-protein interactions []. Yeast Sla2p has been extensively studied: Sla2p arrives at existing endocytic patches with a ~25 seconds delay relative to clathrin and dissociates simultaneously with clathrin upon recruitment of actin-related proteins [, ]. It serves as a bridge, connecting the endocytic patch to the cortical actin cytoskeleton [].
