3. (6pts each) Suppose the following GTPases are mutated so that they permanentl

Question

3. (6pts each) Suppose the following GTPases are mutated so that they permanently bind to GDP. Please predict the location where the stated cargo proteins would accumulate, and provide a brief explanation (2 sentences max). A. GTPase: Ran, Cargo: Protein with NLS sequence Cargo protein location with mutant Ran- Explanation - B. GTPase: Sar1, Cargo: Secreted protein Cargo protein location with mutant Sar - Explanation - C. GTPase: Dynamin, Cargo: Low Density Lipoprotein (LDL) particle Cargo protein location with mutant dynamin Explanation - D. GTPase: ARF1, Cargo: ER Resident protein with KDEL sequence Cargo protein location with mutant ARF1 - Explanation

Explanation / Answer

a) Protein with NLS sequence.

Cargo protein with mutant Ran - Bidirectional transport i.e. import and export of the cargo protein occurs through nuclear pore via a signal sequence - Nuclear localization signal or nuclear export signal. This transport occurs through a GTPase, Ran, which is important for the interaction of the protein with the nuclear pore and its transport through nuclear pore.

If mutant Ran permanently binds to GDP forming Ran-GDP then the cargo protein will remain in the cytosol.

b) Secreted protein

Cargo protein location with mutant Sar1 - COPII coated vesicles consists of GTPase Sar1p, Sec23/24p and Sec13/31p complex that binds to the ER membrane for the anterograde transport from the ER to the Golgi. Budding from the ER involves activation of Sar1p-GDP to Sar1p-GTP by GEF, Sec12p

If Sar1p remains permanently bound to GDP then the cargo protein transport from ER to Golgi will be inhibited and the cargo protein will remain in ER (budding from ER will also be inhibited.)

c) LDL

Cargo protein with mutant dynamin - LDL particles bound to LDL-receptor are transported from the plasma membrane to endosome via clathrin coated vesicles. The release of the vesicle is processed by a cytosolic protein, dynamin. Dynamin polymerizes around the vesicle and then hydrolyzes GTP, which is esssential for the release of vesicle from the plasma membrane .

If dynamin remains bound to GDP then the release of vesicle will be inhibited and the cargo protein will remain in the clathrin coated vesicle.

d) ER resident protein with KDEL sequence

Cargo protein with mutant ARF1 - ARF is an adaptor protein required for the retrograde transport from the golgi to ER through COPI vesicles. Proetin with KDEL sequence (signal sequence for ER resident proteins) that are mistakenly transported to the golgi, is retrieved to the ER by KDEL recognition, in the COPI vesicles.

If ARF1 remains permanently bound to GDP, then the proteins will not be retrieved to the ER and will remain in the golgi.

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