| Structural highlights
4m92 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA.
| | Related: | 4m8g, 4m90, 4m91 |
| Gene: | TUSC3, N33 (HUMAN), IL1RAPL1, OPHN4 (HUMAN) |
| Activity: | Glucokinase, with EC number 2.7.1.2 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Disease
[TUSC3_HUMAN] Autosomal recessive nonsyndromic intellectual deficit. The disease is caused by mutations affecting the gene represented in this entry. [IRPL1_HUMAN] Defects in IL1RAPL1 are the cause of mental retardation X-linked type 21 (MRX21) [MIM:300143]. Mental retardation is a mental disorder characterized by significantly sub-average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period. Non-syndromic mental retardation patients do not manifest other clinical signs.[1] [2]
Function
[TUSC3_HUMAN] Magnesium transporter. May be involved in N-glycosylation through its association with N-oligosaccharyl transferase.[3] [IRPL1_HUMAN] May regulate secretion and presynaptic differentiation through inhibition of the activity of N-type voltage-gated calcium channel. May activate the MAP kinase JNK. Plays a role in presynaptic and postsynaptic differentiation and dendritic spine formation in neurons.[4] [5]
Publication Abstract from PubMed
N-linked glycosylation of proteins in the endoplasmic reticulum (ER) is essential in eukaryotes and catalyzed by oligosaccharyl transferase (OST). Human OST is a hetero-oligomer of seven subunits. The subunit N33/Tusc3 is a tumor suppressor candidate, and defects in the subunit N33/Tusc3 are linked with nonsyndromic mental retardation. Here, we show that N33/Tusc3 possesses a membrane-anchored N-terminal thioredoxin domain located in the ER lumen that may form transient mixed disulfide complexes with OST substrates. X-ray structures of complexes between N33/Tusc3 and two different peptides as model substrates reveal a defined peptide-binding groove adjacent to the active site that can accommodate peptides in opposite orientations. Structural and biochemical data show that N33/Tusc3 prefers peptides bearing a hydrophobic residue two residues away from the cysteine forming the mixed disulfide with N33/Tusc3. Our results support a model in which N33/Tusc3 increases glycosylation efficiency for a subset of human glycoproteins by slowing glycoprotein folding.
Structural basis of substrate specificity of human oligosaccharyl transferase subunit n33/tusc3 and its role in regulating protein N-glycosylation.,Mohorko E, Owen RL, Malojcic G, Brozzo MS, Aebi M, Glockshuber R Structure. 2014 Apr 8;22(4):590-601. doi: 10.1016/j.str.2014.02.013. Epub 2014, Mar 27. PMID:24685145[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Jin H, Gardner RJ, Viswesvaraiah R, Muntoni F, Roberts RG. Two novel members of the interleukin-1 receptor gene family, one deleted in Xp22.1-Xp21.3 mental retardation. Eur J Hum Genet. 2000 Feb;8(2):87-94. PMID:10757639 doi:10.1038/sj.ejhg.5200415
- ↑ Tabolacci E, Pomponi MG, Pietrobono R, Terracciano A, Chiurazzi P, Neri G. A truncating mutation in the IL1RAPL1 gene is responsible for X-linked mental retardation in the MRX21 family. Am J Med Genet A. 2006 Mar 1;140(5):482-7. PMID:16470793 doi:10.1002/ajmg.a.31107
- ↑ Zhou H, Clapham DE. Mammalian MagT1 and TUSC3 are required for cellular magnesium uptake and vertebrate embryonic development. Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15750-5. Epub 2009 Aug 26. PMID:19717468 doi:http://dx.doi.org/0908332106
- ↑ Bahi N, Friocourt G, Carrie A, Graham ME, Weiss JL, Chafey P, Fauchereau F, Burgoyne RD, Chelly J. IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. Hum Mol Genet. 2003 Jun 15;12(12):1415-25. PMID:12783849
- ↑ Khan JA, Brint EK, O'Neill LA, Tong L. Crystal structure of the Toll/interleukin-1 receptor domain of human IL-1RAPL. J Biol Chem. 2004 Jul 23;279(30):31664-70. Epub 2004 Apr 30. PMID:15123616 doi:10.1074/jbc.M403434200
- ↑ Mohorko E, Owen RL, Malojcic G, Brozzo MS, Aebi M, Glockshuber R. Structural basis of substrate specificity of human oligosaccharyl transferase subunit n33/tusc3 and its role in regulating protein N-glycosylation. Structure. 2014 Apr 8;22(4):590-601. doi: 10.1016/j.str.2014.02.013. Epub 2014, Mar 27. PMID:24685145 doi:http://dx.doi.org/10.1016/j.str.2014.02.013
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