This entry includes Rab27a and its highly homologous isoform, Rab27b. Unlike most Rab proteins whose functions remain poorly defined, Rab27a has many known functions. Rab27a has multiple effector proteins, and depending on which effector it binds, Rab27a has different functions as well as tissue distribution and/or cellular localization. Putative functions have been assigned to Rab27a when associated with the effector proteins Slp1, Slp2, Slp3, Slp4, Slp5, DmSlp, rabphilin, Dm/Ce-rabphilin, Slac2-a, Slac2-b, Slac2-c, Noc2, JFC1, and Munc13-4 [, ]. Rab27a has been associated with several human diseases, including hemophagocytic syndrome (Griscelli syndrome or GS), Hermansky-Pudlak syndrome, and choroidermia. In the case of GS, a rare, autosomal recessive disease, a Rab27a mutation is directly responsible for the disorder[]. When Rab27a is localized to the secretory granules of pancreatic beta cells, it is believed to mediate glucose-stimulated insulin secretion, making it a potential target for diabetes therapy [, ]. When bound to JFC1 in prostate cells, Rab27a is believed to regulate the exocytosis of prostate- specific markers [].Rabs are regulated by GTPase activating proteins (GAPs), which interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins [, ].
Noc2, also known as Rabphilin-3A-like protein, is a potential effector of Ras-associated binding proteins Rab3A and Rab27A [, ]that is involved in the regulation of exocytosis in endocrine and exocrine cells [, , ]. Noc2 may regulate insulin secretion from pancreatic beta-cells and amylase secretion from pancreatic acini [].
Synaptotagmin-like protein 5 (SYTL5, also known as Slp5) belongs to the synaptotagmin-like protein family, which contains a N-terminal RabBD (Rab-binding) domain and two C-terminal C2 domains. Slp5 interacts with the GTP-bound form of Rab27A both in vitro and in intact cells. It is highly expressed in human placenta and liver. It may be involved in Rab27A-dependent membrane trafficking in specific tissues [].
Synaptotagmin-like protein 3 (SYTL3, also known as Slp3) belongs to the synaptotagmin-like protein family, which contains a N-terminal RabBD (Rab-binding) domain and two C-terminal C2 domains. Slp3 binds phospholipids in the presence of calcium ions []. In mouse cytotoxic T lymphocytes, Slp3 is an effector of Rab27a and interacts with kinesin-1 through the tetratricopeptide repeat of the kinesin-1 light chain [].
Synaptotagmin-like protein 1 (Slp1/Jfc1) acts as a Rab27a effector and plays a role in vesicle trafficking [, ]. Through its interaction with Rab27a, Slp1 also contributes to secretory lysosome exocytosis from cytotoxic T lymphocytes. Slp1 (and Slp2) may form part of a docking complex, capturing secretory lysosomes at the immunological synapse [].Slp1 possesses two C2 domains in tandem, domain C2A showing homology with the C2B domain of synaptotagmins [].
Synaptotagmin-like protein 2 (SYTL2) belongs to the synaptotagmin-like protein family, which contains a N-terminal RabBD (Rab-binding) domain and two C-terminal C2 domains. RabBD domain mediates interaction with RAB27A and recruitment on to vesicular structures in cytotoxic T-lymphocytes (CTL) [, ]. The C2 domain mediates binding to phosphatidylserine (PS) and phosphatidylinositol 4,5-bisphosphate (PIP2) and localisation to the cell membrane [, ]. SYTL2 has several isoforms produced by alternative splicing, and different isoforms may have different functions.In humans, SYTL2 isoform 1 acts as a RAB27A effector protein and plays a role in cytotoxic granule exocytosis in lymphocytes. It is required for cytotoxic granule docking at the immunologic synapse. Isoform 4 binds phosphatidylserine (PS) and phosphatidylinositol-4,5-bisphosphate (PIP2) and promotes the recruitment of glucagon-containing granules to the cell membrane in pancreatic alpha cells. Its binding to PS is inhibited by Ca2+ while binding to PIP2 is Ca2+ insensitive [, , ]. In mice, SYTL2 isoform 1 may play a role in melanosome transport and vesicle trafficking. It controls melanosome distribution in the cell periphery and regulates melanocyte morphology [, ]. Isoform 1 also acts as a positive mediator of mucus secretion by the surface mucus cells of the stomach. It mediates basal mucus secretion by gastric surface cells by promoting the proper granule biognesis and docking of mucus granules with the apical plasma membrane []. Isoform 11 acts as a RAB27A effector protein and plays a role in cytotoxic granule exocytosis in lymphocytes. It is required for cytotoxic granule docking at the immunologic synapse. Isoform 1 may play a role in melanosome transport and vesicle trafficking. It controls melanosome distribution in the cell periphery and regulates melanocyte morphology.
Synaptotagmin-like protein 5 (SYTL5 or Slp5) is a novel Rab27A-specific effector that is highly expressed in placenta and liver. Slp5 specifically interacted with the GTP-bound form of Rab27A and is involved in Rab27A-dependent membrane trafficking in specific tissues. Slp5 contains an N-terminal Slp homology domain (SHD) and C-terminal tandem C2 domains. The Slp homology domain (SHD) consists of two conserved regions, designated SHD1 (Slp homology domain 1) and SHD2, which may function as protein interaction sites. The SHD1 and SHD2 of Slp5 are separated by a putative FYVE zinc finger, which resembles a FYVE-related domain that is structurally similar to the canonical FYVE domains but lacks the three signature sequences: an N-terminal WxxD motif (x for any residue), the central basic R(R/K)HHCRxCG patch, and a C-terminal RVC motif [].This entry represents the FYVE-related domain found in SYTL5.
Synaptotagmin-like protein 4 (SYTL4, Slp4), also known as granuphilin or exophilin-2, belongs to the synaptotagmin-like protein family (Slp), which is a group of putative membrane trafficking proteins []. The characteristic feature of the Slp family is the N-terminal Slp homology domain (SHD), which functions as a Rab27-binding domain and C-terminal tandem C2 domains (known as the C2A domain and C2B domain), putative Ca2+-binding motifs [, ]. SHD consists of two conserved regions, designated SHD1 and SHD2, which may function as protein interaction sites. The SHD1 and SHD2 of Slp4 are separated by a putative FYVE zinc finger, which resembles a FYVE-related domain that is structurally similar to the canonical FYVE domains but lacks the three signature sequences: an N-terminal WxxD motif (x for any residue), the central basic R(R/K)HHCRxCG patch, and a C-terminal RVC motif.There are several alternatively spliced isoform of Slp4. Slp4-a (granuphilin-a) has two C2 domains, whereas Slp4-b (granuphilin-b) contains only the first C2 domain. Expression of Slp4-a inhibits regulated secretion in endocrine cells. Slp4-a binds to both the GTP- and GDP-bound forms of Rab27A and inhibits a specific GTP/GDP exchange cycle required for dense-core vesicle exocytosis []. Slp4 has been detected in the pancreatic islet, in particular in insulin-positive beta cells, and in pituitary []. This entry represents the FYVE-related domain of synaptotagmin-like protein 4.
Synaptotagmin-like protein 4 (SYTL4, Slp4), also known as granuphilin or exophilin-2, belongs to the synaptotagmin-like protein family (Slp), which is a group of putative membrane trafficking proteins []. The characteristic feature of the Slp family is the N-terminal Slp homology domain (SHD), which functions as a Rab27-binding domain and C-terminal tandem C2 domains (known as the C2A domain and C2B domain), putative Ca2+-binding motifs [, ]. SHD consists of two conserved regions, designated SHD1 and SHD2, which may function as protein interaction sites. The SHD1 and SHD2 of Slp4 are separated by a putative FYVE zinc finger, which resembles a FYVE-related domain that is structurally similar to the canonical FYVE domains but lacks the three signature sequences: an N-terminal WxxD motif (x for any residue), the central basic R(R/K)HHCRxCG patch, and a C-terminal RVC motif.There are several alternatively spliced isoform of Slp4. Slp4-a (granuphilin-a) has two C2 domains, whereas Slp4-b (granuphilin-b) contains only the first C2 domain. Expression of Slp4-a inhibits regulated secretion in endocrine cells. Slp4-a binds to both the GTP- and GDP-bound forms of Rab27A and inhibits a specific GTP/GDP exchange cycle required for dense-core vesicle exocytosis []. Slp4 has been detected inthe pancreatic islet, in particular in insulin-positive beta cells, and in pituitary [].
Melanophilin, also termed SlaC2-a, or exophilin-3, is a GTP-bound form of Rab27A-, myosin Va-, and actin-binding protein present on melanosomes. It is involved in the control of transferring of melanosomes from microtubules to actin filaments. It also functions as a melanocyte type myosin Va (McM5) binding partner and directly activates the actin-activated ATPase activity of McM5 through forming a tripartite protein complex with Rab27A and an actin-based motor myosin Va [,]. SlaC2-a belongs to the Slp homologue lacking C2 domains (Slac2) family. It contains an N-terminal Slp homology domain (SHD), but lacks tandem C2 domains. The SHD consists of two conserved regions, designated SHD1 (Slp homology domain 1) and SHD2, which may function as protein interaction sites []. The SHD1 and SHD2 of SlaC2-a are separated by a putative FYVE zinc finger, which resembles a FYVE-related domain that is structurally similar to the canonical FYVE domains but lacks the three signature sequences: an N-terminal WxxD motif (x for any residue), the central basic R(R/K)HHCRxCG patch, and a C-terminal RVC motif. Moreover, Slac2-a has a middle myosin-binding domain and a C-terminal actin-binding domain [].
