Rangap1Edit

Rangap1, or Ran GTPase-activating protein 1, is a highly conserved regulator of the Ran GTPase cycle that coordinates the directional flow of information between the nucleus and cytoplasm in eukaryotic cells. By catalyzing the hydrolysis of Ran-GTP to Ran-GDP, it helps establish and maintain the Ran gradient that underpins nuclear import and export, and it also participates in spindle assembly and nuclear envelope reassembly during cell division. In humans, Rangap1 is encoded by the RANGAP1 gene and is a key component of the cytoplasmic face of the nuclear pore complex, where its localization is reinforced by post-translational modifications and interactions with other transport factors. Ran RCC1 nuclear transport RanGAP1

Rangap1 sits at the crossroads of nucleo-cytoplasmic transport and mitosis. The Ran GTPase cycle uses Ran-GTP in the nucleus and Ran-GDP in the cytoplasm to regulate the activity of karyopherins that ferry proteins across the nuclear pore complex. RCC1, the Ran guanine nucleotide exchange factor, generates Ran-GTP in the nucleus, while Rangap1 accelerates the conversion of Ran-GTP to Ran-GDP in the cytoplasm. This biochemical polarity enables cargo to be released in the correct compartment and ensures directional traffic for import and export receptors. The system also interfaces with other players such as RanBP1, and a small set of co-factors that tune activity during mitosis. RCC1 RPAP2? RanBP1

Biochemical role and localization - Catalytic action: The GAP (GTPase-activating protein) activity of Rangap1 accelerates hydrolysis of Ran-GTP to Ran-GDP, a reaction central to the disassembly of import complexes and the recycling of transport receptors. This activity is a core feature of many GAP-containing regulators, and it situates Rangap1 as a key driver of the directional cycle. See also GAP (protein) for the broader family context. GAP (protein) - Nuclear pore complex association: Rangap1 localizes predominantly to the cytoplasmic side of the nuclear pore complex in interphase cells. Its positioning is reinforced by post-translational modifications that tether it to NPC components, and by interactions with other transport factors. The interaction network includes RanBP2 (Nup358) and, on occasion, SUMO-modified partners that help stabilize NPC-associated pools. Nup358 SUMO1 farnesylation - Post-translational modifications: Rangap1 undergoes farnesylation of its C-terminal CaaX motif, which promotes membrane-associated localization, and it can be modified by SUMO1 to facilitate docking to the NPC through binding to SUMO-interacting regions on NPC components. These modifications are important for proper subcellular distribution and function. CAAX motif farnesylation SUMO1

Structure and evolution - Domain organization: Rangap1 contains a catalytic GAP domain toward its C-terminus that carries out Ran-GTP hydrolysis, and an N-terminal region that contributes to Ran binding and regulatory interactions. The C-terminal motif responsible for farnesylation anchors the protein to membranes and NPC surfaces. GAP (protein) Ran nuclear envelope - Conservation: The Rangap1 pathway is conserved across a wide range of eukaryotes. In budding yeast, the functional homolog is Rna1, illustrating the deep evolutionary roots of the Ran cycle and its regulators. Comparative studies highlight the essential nature of Ran-directed transport for cell viability and genome integrity. Rna1 Ran evolution

Genetics, expression, and controversies - Gene and expression: In humans, the RANGAP1 gene encodes the Rangap1 protein, which is broadly expressed and fulfills core cellular roles. The precise expression patterns and isoform usage can vary by tissue and developmental stage, reflecting regulation at multiple layers of gene expression. Alternative splicing can yield different transcript variants, a common theme among regulators of essential cellular pathways. RANGAP1 Alternative splicing - Ongoing debates: As with many fundamental regulators of nuclear transport, researchers discuss the relative contributions of Rangap1 to transport versus mitotic functions, and the degree to which distinct subcellular pools (NPC-associated versus cytoplasmic) contribute to observed phenotypes. Some studies emphasize the transport-centric role, while others highlight mitotic and post-m mitotic reassembly roles. These debates center on experimental context, cell type, and the interpretation of localization data. nuclear transport mitosis

Clinical and functional significance - Cellular impact: Proper Rangap1 activity is essential for cargo release and recycling in nucleo-cytoplasmic trafficking, and for the timely reassembly of the nuclear envelope after mitosis. Disruption of RanGAP activity can perturb transport, spindle dynamics, and cell cycle progression, underscoring its central place in cell biology. nuclear transport mitosis - Disease associations: Alterations in the Ran pathway, including aberrant Rangap1 localization or expression, have been described in various disease contexts, notably in cancer biology where misregulation of nuclear transport can accompany oncogenic transformation. The exact causal relationships and therapeutic implications remain areas of active investigation, with ongoing discussion about whether such changes drive disease or reflect downstream consequences of cellular stress. cancer cell cycle

See also - Ran - RCC1 - RanBP1 - RanBP2 - Nup358 - GAP (protein) - nuclear transport - CAAX motif - Rna1 - Alternative splicing