1x9d

From Proteopedia

Crystal Structure Of Human Class I alpha-1,2-Mannosidase In Complex With Thio-Disaccharide Substrate Analogue

Structural highlights

1x9d 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:	X-ray diffraction, Resolution 1.41Å
Ligands:	BU1, CA, MAN, SO4, Z5L
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

MA1B1_HUMAN Defects in MAN1B1 are the cause of mental retardation autosomal recessive type 15 (MRT15) [MIM:614202. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period.^[1]

Function

MA1B1_HUMAN Involved in glycoprotein quality control targeting of misfolded glycoproteins for degradation. It primarily trims a single alpha-1,2-linked mannose residue from Man(9)GlcNAc(2) to produce Man(8)GlcNAc(2), but at high enzyme concentrations, as found in the ER quality control compartment (ERQC), it further trims the carbohydrates to Man(5-6)GlcNAc(2).^[2] ^[3]

Evolutionary Conservation

Checkto colour the structure by Evolutionary Conservation, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Quality control in the endoplasmic reticulum (ER) determines the fate of newly synthesized glycoproteins toward either correct folding or disposal by ER-associated degradation. Initiation of the disposal process involves selective trimming of N-glycans attached to misfolded glycoproteins by ER alpha-mannosidase I and subsequent recognition by the ER degradation-enhancing alpha-mannosidase-like protein family of lectins, both members of glycosylhydrolase family 47. The unusual inverting hydrolytic mechanism catalyzed by members of this family is investigated here by a combination of kinetic and binding analyses of wild type and mutant forms of human ER alpha-mannosidase I as well as by structural analysis of a co-complex with an uncleaved thiodisaccharide substrate analog. These data reveal the roles of potential catalytic acid and base residues and the identification of a novel (3)S(1) sugar conformation for the bound substrate analog. The co-crystal structure described here, in combination with the (1)C(4) conformation of a previously identified co-complex with the glycone mimic, 1-deoxymannojirimycin, indicates that glycoside bond cleavage proceeds through a least motion conformational twist of a properly predisposed substrate in the -1 subsite. A novel (3)H(4) conformation is proposed as the exploded transition state.

Mechanism of class 1 (glycosylhydrolase family 47) {alpha}-mannosidases involved in N-glycan processing and endoplasmic reticulum quality control.,Karaveg K, Siriwardena A, Tempel W, Liu ZJ, Glushka J, Wang BC, Moremen KW J Biol Chem. 2005 Apr 22;280(16):16197-207. Epub 2005 Feb 15. PMID:15713668^[4]

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

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Citations

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References

↑ Rafiq MA, Kuss AW, Puettmann L, Noor A, Ramiah A, Ali G, Hu H, Kerio NA, Xiang Y, Garshasbi M, Khan MA, Ishak GE, Weksberg R, Ullmann R, Tzschach A, Kahrizi K, Mahmood K, Naeem F, Ayub M, Moremen KW, Vincent JB, Ropers HH, Ansar M, Najmabadi H. Mutations in the alpha 1,2-mannosidase gene, MAN1B1, cause autosomal-recessive intellectual disability. Am J Hum Genet. 2011 Jul 15;89(1):176-82. doi: 10.1016/j.ajhg.2011.06.006. PMID:21763484 doi:10.1016/j.ajhg.2011.06.006
↑ Herscovics A, Romero PA, Tremblay LO. The specificity of the yeast and human class I ER alpha 1,2-mannosidases involved in ER quality control is not as strict previously reported. Glycobiology. 2002 Apr;12(4):14G-15G. PMID:12090241
↑ Avezov E, Frenkel Z, Ehrlich M, Herscovics A, Lederkremer GZ. Endoplasmic reticulum (ER) mannosidase I is compartmentalized and required for N-glycan trimming to Man5-6GlcNAc2 in glycoprotein ER-associated degradation. Mol Biol Cell. 2008 Jan;19(1):216-25. Epub 2007 Nov 14. PMID:18003979 doi:10.1091/mbc.E07-05-0505
↑ Karaveg K, Siriwardena A, Tempel W, Liu ZJ, Glushka J, Wang BC, Moremen KW. Mechanism of class 1 (glycosylhydrolase family 47) {alpha}-mannosidases involved in N-glycan processing and endoplasmic reticulum quality control. J Biol Chem. 2005 Apr 22;280(16):16197-207. Epub 2005 Feb 15. PMID:15713668 doi:10.1074/jbc.M500119200