In order for cells to divide at an accelerated rate, as occurs in cancer, they must produce ribosomes, the
machinery for protein production, at an equivalently accelerated rate. Ribosomes are complex molecules that contain
a number of proteins, as well as special pieces of nucleic acid, called ribosomal RNA (rRNA). In fact, these rRNA
molecules are the major components of functional ribosomes and are directly responsible for their activity.
Ribosomal RNA molecules are produced in the cell in a complex, stepwise process, known as rRNA processing.
The lab focuses on studies of molecules required for this processing using X-ray crystallography, as well
as biochemical and biophysical techniques.
The RIO Kinases
The RIO protein kinases are present in all kingdoms of life and are necessary for the fundamental process of ribosome production, yet very little
is known about their function in the cell. The family is characterized by a conserved stretch of roughly ~250 amino acids known as the RIO domain.
The family is further subdivided into at least three subfamilies which contain additional subfamily-specific conserved residues: Rio1 and Rio2
found in all organisms from archaea to human, and Rio3 found only in multi-cellular organisms. A putative fourth subfamily, RioB, is found only
in certain bacteria. The RIO domain is a protein kinase domain which catalyzes the transfer of a phosphate group from adenosine tri-phosphate (ATP)
to the side chain of serine amino acid residues of a protein substrate. However, comparison of the amino acid sequence of RIO proteins with other
protein kinases that catalyze the same reaction showed very little similarity,
and thus RIO kinases were classified as “atypical”. Although it is
known that the cell cannot survive without the RIO kinases and that processing
of rRNA is blocked at a particular step in their absence, the target of their
enzymatic activity is still unknown.
|
|
Current projects in the laboratory include the study of the RIO kinases both structurally and biochemically to learn more about their function.
Through structural studies of the archaeal RIO kinases we have shown that the possibility of designing specific inhibitors of the RIO kinases
is promising because the RIO kinases possess very unique structural features. However, more work is required to determine the structure and
function of the eukaryotic RIO kinases. This includes studies of Rio3, for which there is currently no structural information and only limited
functional information. The objective of our studies will be to determine which parts of the proteins are required for their function, what their
protein substrates are, and how they bind protein substrates to catalyze the phosphoryl transfer reaction. This knowledge will be important for
the understanding of how a critical step in ribosome biogenesis proceeds, and for determining the therapeutic potential of inhibiting the RIO kinases.
|
|
