The structures of the immunity protein Rap1a , responsible for the inhibition and neutralization of Ssp1 endopeptidase, revealed two distinct folds. The structure of the Ssp1-Rap1a complex revealed a tightly bound heteromeric assembly with two effector molecules flanking a Rap1a dimer. The Rap1a subunit displays a compact globular structure constructed from five α-helices that assemble to form the highly stable symmetric dimer [].
The Rap1 subgroup is part of the Rap subfamily of the Ras family. It can be further divided into the Rap1a and Rap1b isoforms. In humans, Rap1a and Rap1b share 95% sequence homology, but are products of two different genes located on chromosomes 1 and 12, respectively. Rap1a is sometimes called smg p21 or Krev1 in the older literature.Rap1 proteins are believed to perform different cellular functions, depending on the isoform, its subcellular localization, and the effector proteins it binds. For example, in rat salivary gland, neutrophils, and platelets, Rap1 localizes to secretory granules and is believed to regulate exocytosis or the formation of secretory granules [, ]. High expression of Rap1 has been observed in the nucleus of human oropharyngeal squamous cell carcinomas (SCCs) and cell lines; interestingly, in the SCCs, the active GTP-bound form localized to the nucleus, while the inactive GDP-bound form localized to the cytoplasm []. Rap1a, which is stimulated by T-cell receptor (TCR) activation, is a positive regulator of T cells by directing integrin activation and augmenting lymphocyte responses []. In murine hippocampal neurons, Rap1b determines which neurite will become the axon and directs the recruitment ofCdc42, which is required for formation of dendrites and axons []. In murine platelets, Rap1b is required for normal homeostasis in vivo and is involved in integrin activation [].
The activity of GTPases is regulated by the opposing effects of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Tuberin (tuberous sclerosis 2 protein or Tsc2) is believed to be a tumor suppressor and is able to stimulate specific GTPases. It stimulates the intrinsic GTPase activity of the Ras-related protein Rap1A and Rab5 [, ]. In complex with Tsc1, inhibits the nutrient-mediated or growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by negatively regulating mTORC1 signaling. It acts as a GTPase-activating protein (GAP) for the small GTPase RheB, a direct activator of the protein kinase activity of mTORC1 [, ]. Ral GTPase-activating protein subunit alpha is the catalytic subunit of the heterodimeric RalGAP complex which acts as a GTPase activator for the Ras-like small GTPases RalA and RalB []. RalGAP complexes share structural and catalytic similarities with the tuberous sclerosis tumor suppressor complex [].
