Crystal structure of Optineurin LIR-fused human LC3B_2-119
Structural highlights
3vtv 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.
OPTN_HUMAN Amyotrophic lateral sclerosis;Congenital glaucoma. Primary open angle glaucoma 1E (GLC1E) [MIM:137760: A form of primary open angle glaucoma (POAG). POAG is characterized by a specific pattern of optic nerve and visual field defects. The angle of the anterior chamber of the eye is open, and usually the intraocular pressure is increased. The disease is asymptomatic until the late stages, by which time significant and irreversible optic nerve damage has already taken place. Note=The disease is caused by mutations affecting the gene represented in this entry.[1][2][3][4][5][6] Normal pressure glaucoma (NPG) [MIM:606657: A primary glaucoma characterized by intraocular pression consistently within the statistically normal population range. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.[7] Amyotrophic lateral sclerosis 12 (ALS12) [MIM:613435: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. Note=The disease is caused by mutations affecting the gene represented in this entry.[8]
Function
MLP3B_HUMAN Involved in formation of autophagosomal vacuoles (autophagosomes).OPTN_HUMAN Plays an important role in the maintenance of the Golgi complex, in membrane trafficking, in exocytosis, through its interaction with myosin VI and Rab8. Links myosin VI to the Golgi complex and plays an important role in Golgi ribbon formation. Negatively regulates the induction of IFNB in response to RNA virus infection. Plays a neuroprotective role in the eye and optic nerve. Probably part of the TNF-alpha signaling pathway that can shift the equilibrium toward induction of cell death. May act by regulating membrane trafficking and cellular morphogenesis via a complex that contains Rab8 and hungtingtin (HD). May constitute a cellular target for adenovirus E3 14.7, an inhibitor of TNF-alpha functions, thereby affecting cell death.[9][10][11]
Publication Abstract from PubMed
Selective autophagy is mediated by the interaction of autophagy modifiers and autophagy receptors that also bind to ubiquitinated cargo. Optineurin is an autophagy receptor that plays a role in the clearance of cytosolic Salmonella. The interaction between receptors and modifiers is often relatively weak, with typical values for the dissociation constant in the low micromolar range. The interaction of optineurin with autophagy modifiers is even weaker but can be significantly enhanced through phosphorylation by the TANK binding kinase 1. Here we present the NMR and crystal structures of the autophagy modifier LC3B in complex with the LC3 interaction region of optineurin either phosphorylated or bearing phospho-mimicking mutations. The structures show that the negative charge induced by phosphorylation is recognized by the side-chains of Arg11 and Lys51 in LC3B. Further mutational analysis suggests that the replacement of the canonical Trp side chain of autophagy receptors with the smaller Phe side chain in optineurin significantly weakens its interaction with the autophagy modifier LC3B. Through phosphorylation of serines directly N-terminally located to the Phe residue, the affinity is increased to the level normally seen for receptor - modifier interactions. Phosphorylation, therefore, acts as a switch for optineurin-based selective autophagy.
Structural basis for phosphorylation-triggered autophagic clearance of Salmonella.,Rogov VV, Suzuki H, Fiskin E, Wild P, Kniss A, Rozenknop A, Kato R, Kawasaki M, McEwan DG, Lohr F, Guntert P, Dikic I, Wakatsuki S, Dotsch V Biochem J. 2013 Jun 28. PMID:23805866[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑ Rezaie T, Child A, Hitchings R, Brice G, Miller L, Coca-Prados M, Heon E, Krupin T, Ritch R, Kreutzer D, Crick RP, Sarfarazi M. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science. 2002 Feb 8;295(5557):1077-9. PMID:11834836 doi:10.1126/science.1066901
↑ Leung YF, Fan BJ, Lam DS, Lee WS, Tam PO, Chua JK, Tham CC, Lai JS, Fan DS, Pang CP. Different optineurin mutation pattern in primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 2003 Sep;44(9):3880-4. PMID:12939304
↑ Alward WL, Kwon YH, Kawase K, Craig JE, Hayreh SS, Johnson AT, Khanna CL, Yamamoto T, Mackey DA, Roos BR, Affatigato LM, Sheffield VC, Stone EM. Evaluation of optineurin sequence variations in 1,048 patients with open-angle glaucoma. Am J Ophthalmol. 2003 Nov;136(5):904-10. PMID:14597044
↑ Willoughby CE, Chan LL, Herd S, Billingsley G, Noordeh N, Levin AV, Buys Y, Trope G, Sarfarazi M, Heon E. Defining the pathogenicity of optineurin in juvenile open-angle glaucoma. Invest Ophthalmol Vis Sci. 2004 Sep;45(9):3122-30. PMID:15326130 doi:10.1167/iovs.04-0107
↑ Funayama T, Ishikawa K, Ohtake Y, Tanino T, Kurosaka D, Kimura I, Suzuki K, Ideta H, Nakamoto K, Yasuda N, Fujimaki T, Murakami A, Asaoka R, Hotta Y, Tanihara H, Kanamoto T, Mishima H, Fukuchi T, Abe H, Iwata T, Shimada N, Kudoh J, Shimizu N, Mashima Y. Variants in optineurin gene and their association with tumor necrosis factor-alpha polymorphisms in Japanese patients with glaucoma. Invest Ophthalmol Vis Sci. 2004 Dec;45(12):4359-67. PMID:15557444 doi:45/12/4359
↑ Fuse N, Takahashi K, Akiyama H, Nakazawa T, Seimiya M, Kuwahara S, Tamai M. Molecular genetic analysis of optineurin gene for primary open-angle and normal tension glaucoma in the Japanese population. J Glaucoma. 2004 Aug;13(4):299-303. PMID:15226658
↑ Umeda T, Matsuo T, Nagayama M, Tamura N, Tanabe Y, Ohtsuki H. Clinical relevance of optineurin sequence alterations in Japanese glaucoma patients. Ophthalmic Genet. 2004 Jun;25(2):91-9. PMID:15370540 doi:10.1080/13816810490514298
↑ Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, Komure O, Matsuura S, Kobatake K, Morimoto N, Abe K, Suzuki N, Aoki M, Kawata A, Hirai T, Kato T, Ogasawara K, Hirano A, Takumi T, Kusaka H, Hagiwara K, Kaji R, Kawakami H. Mutations of optineurin in amyotrophic lateral sclerosis. Nature. 2010 May 13;465(7295):223-6. doi: 10.1038/nature08971. Epub 2010 Apr 28. PMID:20428114 doi:10.1038/nature08971
↑ Rezaie T, Child A, Hitchings R, Brice G, Miller L, Coca-Prados M, Heon E, Krupin T, Ritch R, Kreutzer D, Crick RP, Sarfarazi M. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science. 2002 Feb 8;295(5557):1077-9. PMID:11834836 doi:10.1126/science.1066901
↑ Sahlender DA, Roberts RC, Arden SD, Spudich G, Taylor MJ, Luzio JP, Kendrick-Jones J, Buss F. Optineurin links myosin VI to the Golgi complex and is involved in Golgi organization and exocytosis. J Cell Biol. 2005 Apr 25;169(2):285-95. Epub 2005 Apr 18. PMID:15837803 doi:10.1083/jcb.200501162
↑ Mankouri J, Fragkoudis R, Richards KH, Wetherill LF, Harris M, Kohl A, Elliott RM, Macdonald A. Optineurin negatively regulates the induction of IFNbeta in response to RNA virus infection. PLoS Pathog. 2010 Feb 19;6(2):e1000778. doi: 10.1371/journal.ppat.1000778. PMID:20174559 doi:10.1371/journal.ppat.1000778
↑ Rogov VV, Suzuki H, Fiskin E, Wild P, Kniss A, Rozenknop A, Kato R, Kawasaki M, McEwan DG, Lohr F, Guntert P, Dikic I, Wakatsuki S, Dotsch V. Structural basis for phosphorylation-triggered autophagic clearance of Salmonella. Biochem J. 2013 Jun 28. PMID:23805866 doi:10.1042/BJ20121907
