Alternative titles; symbols
HGNC Approved Gene Symbol: HOOK2
Cytogenetic location: 19p13.13 Genomic coordinates (GRCh38): 19:12,763,003-12,792,350 (from NCBI)
Hook proteins are cytosolic coiled-coil proteins that contain conserved N-terminal domains, which attach to microtubules, and more divergent C-terminal domains, which mediate binding to organelles. The Drosophila Hook protein is a component of the endocytic compartment (summary by Walenta et al., 2001).
Using homology with the Drosophila Hook gene, Kramer and Phistry (1999) identified ESTs containing the HOOK2 sequence, which they called HK2. By 5-prime RACE of a placenta cDNA library, they cloned a full-length HOOK2 cDNA. The deduced 728-amino acid protein contains an N-terminal domain, a central coiled-coil domain, and a C-terminal domain. HOOK2 shares 30% identity with Drosophila Hook, with highest conservation in the N-terminal domain. Kramer and Phistry (1999) also identified a shorter, alternatively spliced transcript.
By Western blot analysis, Walenta et al. (2001) determined that endogenous HOOK2 detected in HEK293 cells had an apparent molecular mass of about 83 kD. Endogenous HOOK2 localized to discrete punctate subcellular structures that were often observed in linear tracks that colocalized with microtubule markers.
Gross (2023) mapped the HOOK3 gene to chromosome 19p13.13 based on an alignment of the HOOK3 sequence (GenBank BC012443) with the genomic sequence (GRCh38).
By Western blot analysis of HEK293 immunoprecipitates, Walenta et al. (2001) determined that HOOK2 exists in a protein complex that is distinct from complexes containing HOOK1 (607820) and HOOK3 (607825). By microtubule spin-down assay, they determined that full-length HOOK2 and a C-terminal truncation mutant bound to microtubules.
By pull-down, immunoprecipitation, and yeast 2-hybrid analyses, Mattera et al. (2020) showed that the heterotetrameric adaptor protein complex-4 (AP4; see 607244) interacted with an FTS (AKTIP; 608483)-HOOK-FHIP (FHF) complex containing FHIP (FHIP1B; 620229), FTS, HOOK1, HOOK2, and HOOK3. The interaction was mediated by direct binding between the mu-4 subunit of AP4 (AP4M1; 602296) and the HOOK1 and HOOK2 subunits of FHF. Deletion mapping revealed that 2 coiled-coiled domains in HOOK1 were necessary and sufficient for interaction with mu-4, as well as with HOOK1 and HOOK3. HOOK2 and AP4 colocalized in the perinuclear area of Hela cells. Knockdown of FHF subunits resulted in dispersal of AP4 and ATG9A (612204) from the perinuclear region toward the periphery in Hela cells, indicating that the FHF complex interacted with AP4 to mediate perinuclear distribution of AP4 and its cargo, ATG9A. Moreover, dispersal of ATG9A affected autophagy in FHF-depleted cells.
By immunoprecipitation and mass spectrometric analyses in 293T cell lines, Christensen et al. (2021) showed that different FHIP proteins associated with diverse cellular interactomes. Moreover, different FHIP proteins interacted with different HOOKs to generate preferential formation of different FHF complexes: FHIP1A and FHIP1B formed a complex with HOOK1 and HOOK3, FHIP2A (617312) preferentially associated with HOOK2, and FHIP2B appeared capable of forming a complex with HOOK1, HOOK2, and HOOK3. These FHF complexes associated with moving dynein/dynactin complexes, with FHIP2A preferentially interacting with HOOK2, and FHIP1B interacting with HOOK3, to form FHF complexes that associated with motile dynein/dynactin. Expression of FHIP1B or FHIP2A in human U2OS cells deficient in their respective genes revealed that FHIP1B and FHIP2A colocalized with microtubule-associated cargoes with different morphologies to determine cargo specificity of dynein. FHIP1B functioned as a RAB5-specific effector and associated with early endosomes via direct interaction with GTP-bound RAB5B. In contrast, FHIP2A formed a complex predominantly with HOOK2 to link dynein to RAB1A (RAB1; 179508)-bound endoplasmic reticulum-to-Golgi tubular intermediates.
Christensen, J. R., Kendrick, A. A., Truong, J. B., Aguilar-Maldonado, A., Adani, V., Dzieciatkowska, M., Reck-Peterson, S. L. Cytoplasmic dynein-1 cargo diversity is mediated by the combinatorial assembly of FTS-Hook-FHIP complexes. eLife 10: e74538, 2021. [PubMed: 34882091] [Full Text: https://doi.org/10.7554/eLife.74538]
Gross, M. B. Personal Communication. Baltimore, Md. 1/31/2023.
Kramer, H., Phistry, M. Genetic analysis of hook, a gene required for endocytic trafficking in Drosophila. Genetics 151: 675-684, 1999. [PubMed: 9927460] [Full Text: https://doi.org/10.1093/genetics/151.2.675]
Mattera, R., Williamson, C. D., Ren, X., Bonifacino, J. S. The FTS-Hook-FHIP (FHF) complex interacts with AP-4 to mediate perinuclear distribution of AP-4 and its cargo ATG9A. Molec. Biol. Cell 31: 963-979, 2020. [PubMed: 32073997] [Full Text: https://doi.org/10.1091/mbc.E19-11-0658]
Walenta, J. H., Didier, A. J., Liu, X., Kramer, H. The Golgi-associated Hook3 protein is a member of a novel family of microtubule-binding proteins. J. Cell Biol. 152: 923-934, 2001. [PubMed: 11238449] [Full Text: https://doi.org/10.1083/jcb.152.5.923]