6ulg

Cryo-EM structure of the FLCN-FNIP2-Rag-Ragulator complexCryo-EM structure of the FLCN-FNIP2-Rag-Ragulator complex

6ulg, resolution 3.31Å

Structural highlights

6ulg is a 9 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.31Å
Ligands:
Experimental data:	Check
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

FLCN_HUMAN Familial spontaneous pneumothorax;Birt-Hogg-Dube syndrome. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The gene represented in this entry may be involved in disease pathogenesis.

Function

FLCN_HUMAN May play a role in the pathogenesis of an uncommon form of kidney cancer through its association with an inherited disorder of the hair follicle (fibrofolliculomas). May be a tumor suppressor. May be involved in colorectal tumorigenesis. May be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways. May regulate phosphorylation of RPS6KB1.^[1] ^[2] ^[3]

Publication Abstract from PubMed

mTORC1 controls anabolic and catabolic processes in response to nutrients through the Rag GTPase heterodimer, which is regulated by multiple upstream protein complexes. One such regulator, FLCN-FNIP2, is a GTPase activating protein (GAP) for RagC/D, but despite its important role, how it activates the Rag GTPase heterodimer remains unknown. We used cryo-EM to determine the structure of FLCN-FNIP2 in a complex with the Rag GTPases and Ragulator. FLCN-FNIP2 adopts an extended conformation with two pairs of heterodimerized domains. The Longin domains heterodimerize and contact both nucleotide binding domains of the Rag heterodimer, while the DENN domains interact at the distal end of the structure. Biochemical analyses reveal a conserved arginine on FLCN as the catalytic arginine finger and lead us to interpret our structure as an on-pathway intermediate. These data reveal features of a GAP-GTPase interaction and the structure of a critical component of the nutrient-sensing mTORC1 pathway.

Cryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Complex.,Shen K, Rogala KB, Chou HT, Huang RK, Yu Z, Sabatini DM Cell. 2019 Nov 5. pii: S0092-8674(19)31213-9. doi: 10.1016/j.cell.2019.10.036. PMID:31704029^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, Duray P, Merino M, Choyke P, Pavlovich CP, Sharma N, Walther M, Munroe D, Hill R, Maher E, Greenberg C, Lerman MI, Linehan WM, Zbar B, Schmidt LS. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome. Cancer Cell. 2002 Aug;2(2):157-64. PMID:12204536
↑ Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, Esposito D, Gillette WK, Hopkins RF 3rd, Hartley JL, Furihata M, Oishi S, Zhen W, Burke TR Jr, Linehan WM, Schmidt LS, Zbar B. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15552-7. Epub 2006 Oct 6. PMID:17028174 doi:http://dx.doi.org/0603781103
↑ Takagi Y, Kobayashi T, Shiono M, Wang L, Piao X, Sun G, Zhang D, Abe M, Hagiwara Y, Takahashi K, Hino O. Interaction of folliculin (Birt-Hogg-Dube gene product) with a novel Fnip1-like (FnipL/Fnip2) protein. Oncogene. 2008 Sep 11;27(40):5339-47. doi: 10.1038/onc.2008.261. Epub 2008 Jul, 28. PMID:18663353 doi:http://dx.doi.org/10.1038/onc.2008.261
↑ Shen K, Rogala KB, Chou HT, Huang RK, Yu Z, Sabatini DM. Cryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Complex. Cell. 2019 Nov 5. pii: S0092-8674(19)31213-9. doi: 10.1016/j.cell.2019.10.036. PMID:31704029 doi:http://dx.doi.org/10.1016/j.cell.2019.10.036

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, Duray P, Merino M, Choyke P, Pavlovich CP, Sharma N, Walther M, Munroe D, Hill R, Maher E, Greenberg C, Lerman MI, Linehan WM, Zbar B, Schmidt LS. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome. Cancer Cell. 2002 Aug;2(2):157-64. PMID:12204536

[2] Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, Esposito D, Gillette WK, Hopkins RF 3rd, Hartley JL, Furihata M, Oishi S, Zhen W, Burke TR Jr, Linehan WM, Schmidt LS, Zbar B. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15552-7. Epub 2006 Oct 6. PMID:17028174 doi:http://dx.doi.org/0603781103

[3] Takagi Y, Kobayashi T, Shiono M, Wang L, Piao X, Sun G, Zhang D, Abe M, Hagiwara Y, Takahashi K, Hino O. Interaction of folliculin (Birt-Hogg-Dube gene product) with a novel Fnip1-like (FnipL/Fnip2) protein. Oncogene. 2008 Sep 11;27(40):5339-47. doi: 10.1038/onc.2008.261. Epub 2008 Jul, 28. PMID:18663353 doi:http://dx.doi.org/10.1038/onc.2008.261

[4] Shen K, Rogala KB, Chou HT, Huang RK, Yu Z, Sabatini DM. Cryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Complex. Cell. 2019 Nov 5. pii: S0092-8674(19)31213-9. doi: 10.1016/j.cell.2019.10.036. PMID:31704029 doi:http://dx.doi.org/10.1016/j.cell.2019.10.036

[1]

[2]

[3]

[4]