7lk4

From Proteopedia

Crystal structure of BAK L100A in complex with activating antibody fragments

Structural highlights

7lk4 is a 12 chain structure with sequence from Homo sapiens and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.1Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

BAK_HUMAN In the presence of an appropriate stimulus, accelerates programmed cell death by binding to, and antagonizing the anti-apoptotic action of BCL2 or its adenovirus homolog E1B 19k protein. Low micromolar levels of zinc ions inhibit the promotion of apoptosis.^[1] ^[2]

Publication Abstract from PubMed

Pro-apoptotic BAK and BAX are activated by BH3-only proteins to permeabilise the outer mitochondrial membrane. The antibody 7D10 also activates BAK on mitochondria and its epitope has previously been mapped to BAK residues in the loop connecting helices alpha1 and alpha2 of BAK. A crystal structure of the complex between the Fv fragment of 7D10 and the BAK mutant L100A suggests a possible mechanism of activation involving the alpha1-alpha2 loop residue M60. M60 mutants of BAK have reduced stability and elevated sensitivity to activation by BID, illustrating that M60, through its contacts with residues in helices alpha1, alpha5 and alpha6, is a linchpin stabilising the inert, monomeric structure of BAK. Our data demonstrate that BAK's alpha1-alpha2 loop is not a passive covalent connector between secondary structure elements, but a direct restraint on BAK's activation.

Structure of the BAK-activating antibody 7D10 bound to BAK reveals an unexpected role for the alpha1-alpha2 loop in BAK activation.,Robin AY, Miller MS, Iyer S, Shi MX, Wardak AZ, Lio D, Smith NA, Smith BJ, Birkinshaw RW, Czabotar PE, Kluck RM, Colman PM Cell Death Differ. 2022 Sep;29(9):1757-1768. doi: 10.1038/s41418-022-00961-w. , Epub 2022 Mar 12. PMID:35279694^[3]

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

References

↑ Chittenden T, Flemington C, Houghton AB, Ebb RG, Gallo GJ, Elangovan B, Chinnadurai G, Lutz RJ. A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions. EMBO J. 1995 Nov 15;14(22):5589-96. PMID:8521816
↑ Moldoveanu T, Liu Q, Tocilj A, Watson M, Shore G, Gehring K. The X-ray structure of a BAK homodimer reveals an inhibitory zinc binding site. Mol Cell. 2006 Dec 8;24(5):677-88. PMID:17157251 doi:10.1016/j.molcel.2006.10.014
↑ Robin AY, Miller MS, Iyer S, Shi MX, Wardak AZ, Lio D, Smith NA, Smith BJ, Birkinshaw RW, Czabotar PE, Kluck RM, Colman PM. Structure of the BAK-activating antibody 7D10 bound to BAK reveals an unexpected role for the alpha1-alpha2 loop in BAK activation. Cell Death Differ. 2022 Mar 12. pii: 10.1038/s41418-022-00961-w. doi:, 10.1038/s41418-022-00961-w. PMID:35279694 doi:http://dx.doi.org/10.1038/s41418-022-00961-w