Yale scientists identify structure for RNA quality control

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Yale scientists identify structure for RNA quality control

Illustration of Ro with RNAs (pink & green) in surface binding sites

and misfolded RNA (aqua) in the 'hole'

Full size image available here

New Haven, Conn. -- A report by Yale scientists in the journal Cell

sheds new light on how the protein Ro, a major autoantigen in patients

with autoimmune disease, recognizes misfolded RNAs, creating a RNA

quality control system for cells.

The quality control process in the cell has been well-studied for the

DNA and messenger RNA (mRNA) components for making proteins. However,

little was known about what cells do with abnormal or misfolded RNAs

that are not translated into protein -- such as ribosomal RNAs (rRNAs),

transfer RNAs (tRNAs), and small nuclear and cytoplasmic regulatory

RNAs. This work describes a molecular mechanism of RNA quality control.

In the autoimmune disorders systemic lupus erythematosus and Sjogren's

syndrome, Ro is known to be an autoantigen, and autoimmune disease

develops in mice that lack Ro protein. This study demonstrated a

connection between binding of normal RNA and " disposal " of abnormal and

misfolded RNAs by Ro protein.

Collaboration between the laboratories of Assistant Professor Karin M.

Reinisch and Associate Professor L. Wolin in the department of

Cell Biology used both crystallography and biochemistry to visualize

how Ro interacts with these RNAs.

" The crystal structures of Ro revealed two distinct RNA binding sites,

one of which recognizes misfolded small RNAs. Unlike most proteins, Ro

has a hole through the middle - and the hole is used in distinguishing

these RNAs, " said Reinisch.

Mothers with anti-Ro antibodies often have babies with heart signal

conduction defects; some scientists believe that the antibodies may

cause the defects. " Although Ro is a major human autoantigen, how the

molecule is recognized by patient autoantibodies was not fully

determined. So, understanding these features of the Ro protein may

allow the design of drugs to block the interaction between the

antibodies and Ro, " said Wolin.

The research team consisted of members from the Reinisch and Wolin lab

groups-- Adam J. Stein, e Fuchs, Chumei Fu. Wolin is also an

investigator of the Medical Institute. The work was

funded by grants from the G. Harold and Leila Y. Mathers Foundation,

the Pew Charitable Trust, and the National Institutes of Health.

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Citation: Cell 121: 529 - 539 (May 20, 2005)