Clearer Understanding of DNA Replication Origin Recognition Complex (ORC), As Well As Related Meier-Gorlin Genetic Dwarfism Syndrome Offered by Atomic-Level Resolution Analysis of ORC Crystal Structure

A clearer understanding of the origin recognition complex (ORC) - a protein complex that directs DNA replication - through its crystal structure offers new insight into fundamental mechanisms of DNA replication initiation. This will also provide insight into how ORC may be compromised in a subset of patients with Meier-Gorlin syndrome, a form of dwarfism in humans. ORC is a six-subunit protein complex that directly binds DNA to recruit other protein factors involved in DNA replication. Researchers collected data at the Advanced Photon Source (APS), a U.S. Department of Energy User Facility based at Argonne National Laboratory in Illinois, to obtain the first atomic-level resolution picture of this complex. The structure shows that ORC's main body has five subunits that contain a common fold that is found in proteins binding ATP, a small molecule that cells use as fuel. One of the largest subunits, ORC3, has a structural element that protrudes from the ORC core to contact ORC6, according to the paper, "Crystal Structure of the Eukaryotic Origin Recognition Complex," which was published in the March 19, 2015 issue of in Nature. "The crystal structure explains why a mutation in ORC6 that is linked to Meier-Gorlin syndrome in a subset of patients results in defective binding of this subunit to ORC3," said Dr. Franziska Bleichert, the paper's lead author. "The structure also makes specific predictions on how the different ORC protein subunits might interact with DNA in the central channel of ORC and with other replication initiation factors."
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