Practice question

Small GTPases act as molecular switches whose effector binding depends on nucleotide state. Intrinsic exchange of GDP for GTP is extremely slow, requiring catalysts. Guanine nucleotide exchange factors bind inactive GDP-bound GTPase, distort P-loop, magnesium coordination and switch regions, lowering affinity for GDP by several orders of magnitude and permitting release. Because cytosolic GTP is roughly tenfold more abundant than GDP, GTP quickly occupies empty pocket, inducing active conformation where switch I and switch II reposition to bind effectors. Nuclear RCC1 for Ran produces high nuclear Ran-GTP gradient essential for transport, Sec12 for Sar1 initiates COPII at ER, GBF1 and BIGs for Arf1 recruit COPI, Rabex-5 for Rab5 drives early endosome fusion, RhoGEFs for Rho control actin. After signaling, GTPase activating proteins insert catalytic arginine accelerating hydrolysis to GDP terminating interaction. Degradation of misfolded proteins, ribosome anchoring to ER or blocking nuclear import are unrelated. Thus converting GDP-bound inactive form to GTP-bound active form captures core biochemical definition of GEF action across trafficking, cytoskeletal and signaling networks, explaining spatial control of activation and timing of downstream effector recruitment and pathway progression.