6kvg
The solution structure of human Orc6
Structural highlights
DiseaseORC6_HUMAN Ear-patella-short stature syndrome. Defects in ORC6 are the cause of Meier-Gorlin syndrome type 3 (MGORS3) [MIM:613803. MGORS3 is a syndrome characterized by bilateral microtia, aplasia/hypoplasia of the patellae, and severe intrauterine and postnatal growth retardation with short stature and poor weight gain. Additional clinical findings include anomalies of cranial sutures, microcephaly, apparently low-set and simple ears, microstomia, full lips, highly arched or cleft palate, micrognathia, genitourinary tract anomalies, and various skeletal anomalies. While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal.[1] FunctionORC6_HUMAN Component of the origin recognition complex (ORC) that binds origins of replication. DNA-binding is ATP-dependent, however specific DNA sequences that define origins of replication have not been identified so far. ORC is required to assemble the pre-replication complex necessary to initiate DNA replication. Publication Abstract from PubMedThe six-subunit origin recognition complex (ORC), a DNA replication initiator, defines the localization of the origins of replication in eukaryotes. The Orc6 subunit is the smallest and the least conserved among ORC subunits. It is required for DNA replication and essential for viability in all species. Orc6 in metazoans carries a structural homology with transcription factor TFIIB and can bind DNA on its own. Here, we report a solution structure of the full-length human Orc6 (HsOrc6) alone and in a complex with DNA. We further showed that human Orc6 is composed of three independent domains: N-terminal, middle and C-terminal (HsOrc6-N, HsOrc6-M and HsOrc6-C). We also identified a distinct DNA-binding domain of human Orc6, named as HsOrc6-DBD. The detailed analysis of the structure revealed novel amino acid clusters important for the interaction with DNA. Alterations of these amino acids abolish DNA-binding ability of Orc6 and result in reduced levels of DNA replication. We propose that Orc6 is a DNA-binding subunit of human/metazoan ORC and may play roles in targeting, positioning and assembling the functional ORC at the origins. Structural basis of DNA replication origin recognition by human Orc6 protein binding with DNA.,Xu N, You Y, Liu C, Balasov M, Lun LT, Geng Y, Fung CP, Miao H, Tian H, Choy TT, Shi X, Fan Z, Zhou B, Akhmetova K, Din RU, Yang H, Hao Q, Qian P, Chesnokov I, Zhu G Nucleic Acids Res. 2020 Sep 28. pii: 5912572. doi: 10.1093/nar/gkaa751. PMID:32986843[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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