8tzs

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Structure of human WLS

Structural highlights

8tzs is a 1 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 3.84Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

WLS_HUMAN The disease is caused by variants affecting the gene represented in this entry.

Function

WLS_HUMAN Regulates Wnt proteins sorting and secretion in a feedback regulatory mechanism. This reciprocal interaction plays a key role in the regulation of expression, subcellular location, binding and organelle-specific association of Wnt proteins (PubMed:34587386). Plays also an important role in establishment of the anterior-posterior body axis formation during development (By similarity).^[1] ^[2] ^[3]

Publication Abstract from PubMed

Wnt proteins are enzymatically lipidated by Porcupine (PORCN) in the ER and bind to Wntless (WLS) for intracellular transport and secretion. Mechanisms governing the transfer of these low-solubility Wnts from the ER to the extracellular space remain unclear. Through structural and functional analyses of Wnt7a, a crucial Wnt involved in central nervous system angiogenesis and blood-brain barrier maintenance, we have elucidated the principles of Wnt biogenesis and Wnt7-specific signaling. The Wnt7a-WLS complex binds to calreticulin (CALR), revealing that CALR functions as a chaperone to facilitate Wnt transfer from PORCN to WLS during Wnt biogenesis. Our structures, functional analyses, and molecular dynamics simulations demonstrate that a phospholipid in the core of Wnt-bound WLS regulates the association and dissociation between Wnt and WLS, suggesting a lipid-mediated Wnt secretion mechanism. Finally, the structure of Wnt7a bound to RECK, a cell-surface Wnt7 co-receptor, reveals how RECK(CC4) engages the N-terminal domain of Wnt7a to activate Wnt7-specific signaling.

Molecular basis of Wnt biogenesis, secretion, and Wnt7-specific signaling.,Qi X, Hu Q, Elghobashi-Meinhardt N, Long T, Chen H, Li X Cell. 2023 Nov 9;186(23):5028-5040.e14. doi: 10.1016/j.cell.2023.09.021. Epub , 2023 Oct 17. PMID:37852257^[4]

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

References

↑ Bänziger C, Soldini D, Schütt C, Zipperlen P, Hausmann G, Basler K. Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells. Cell. 2006 May 5;125(3):509-22. PMID:16678095 doi:10.1016/j.cell.2006.02.049
↑ Bartscherer K, Pelte N, Ingelfinger D, Boutros M. Secretion of Wnt ligands requires Evi, a conserved transmembrane protein. Cell. 2006 May 5;125(3):523-33. PMID:16678096 doi:10.1016/j.cell.2006.04.009
↑ Chai G, Szenker-Ravi E, Chung C, Li Z, Wang L, Khatoo M, Marshall T, Jiang N, Yang X, McEvoy-Venneri J, Stanley V, Anzenberg P, Lang N, Wazny V, Yu J, Virshup DM, Nygaard R, Mancia F, Merdzanic R, Toralles MBP, Pitanga PML, Puri RD, Hernan R, Chung WK, Bertoli-Avella AM, Al-Sannaa N, Zaki MS, Willert K, Reversade B, Gleeson JG. A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion. N Engl J Med. 2021 Sep 30;385(14):1292-1301. PMID:34587386 doi:10.1056/NEJMoa2033911
↑ Qi X, Hu Q, Elghobashi-Meinhardt N, Long T, Chen H, Li X. Molecular basis of Wnt biogenesis, secretion, and Wnt7-specific signaling. Cell. 2023 Nov 9;186(23):5028-5040.e14. PMID:37852257 doi:10.1016/j.cell.2023.09.021