Philadelphia University + Thomas Jefferson University

Hou, Ya-Ming

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Ya-Ming Hou, PhD

Contact Dr. Hou

900 Walnut Street
JHN 4th floor
Philadelphia, PA 19107

(215) 503-4480
(215) 923-9162 fax

Research and Clinical Interests

Mechanisms of tRNA functions and protein synthesis by the ribosome

Functions of tRNA in protein synthesis. My research focuses on understanding the structure-function activities of tRNAs, which are the L-shaped adaptors between mRNA and protein sequences during genetic decoding. During decoding, a tRNA is charged with a specific amino acid to form an aminoacyl-tRNA, which enters the ribosome at a codon position cognate to the anticodon. In the ribosome, the charged tRNA donates its amino acid to peptide bond formation and then transits through. The entire process is complex, dynamics, and includes different tRNA activities and functions that are achieved by interactions with various protein partners.

Perturbation of protein synthesis leads to neurodegenerate diseases. In neurons, the protein synthesis machinery can occur near the cell body or in distal and local neuronal processes. The local protein synthesis has been implicated in many aspects of neuronal development and functions, such as axon guidance, dendritic elaboration, synaptic plasticity, and long-term memory formation. Dysfunction of protein synthesis has been implicated in human neurological disorders, such as fragile X syndrome, Charcot-Marie-Tooth disease, spinal muscular atrophy, and various mitochondrial dysfunctions.

What determines successful protein synthesis? The key determinant for successful protein synthesis is a delicate balance between speed (~10 amino acids per sec) and specificity (at an error rate of 10-4). To ensure this balance, we are studying four key steps. The first is aminoacylation of tRNA catalyzed by aminoacyl-tRNA synthetases. Mutations in the aminoacylation reaction can lead to protein misfolding and neuro-degeneration as manifested in the Charcot-Marie-Tooth neuropathy. Second, we are studying the m1G37 methyl transferase, which uses the methyl group of S-adenosyl methionine to form the m1G37 modification adjacent to the anticodon of a subset of tRNAs, which is essential for the decoding specificity. Mutations that perturb this modification lead to cell death. Third, we are studying the tRNA 3' end maturation reaction, catalyzed by the CCA-adding enzyme, which renders tRNA eligible for protein synthesis. We have shown that this CCA maturation provides a kinetic quality control that rejects damaged tRNA from protein synthesis. Fourth, we are investigating how tRNA-ribosome communicates during translocation to understand the basis of specificity.

Publications

Most Recent Peer-Reviewed Publications

  1. Initiator tRNA genes template the 3' CCA end at high frequencies in bacteria
  2. Methyl transfer by substrate signaling from a knotted protein fold
  3. Molecular basis and consequences of the cytochrome c-tRNA interaction
  4. A novel HSD17B10 mutation impairing the activities of the mitochondrial Rnase P complex causes X-linked intractable epilepsy and neurodevelopmental regression
  5. Kinetic Analysis of tRNA Methyltransferases
  6. Structural basis for methyl-donor-dependent and sequence-specific binding to tRNA substrates by knotted methyltransferase TrmD
  7. The UGG isoacceptor of tRNAPro is naturally prone to frameshifts
  8. Maintenance of protein synthesis reading frame by EF-P and m 1 G37-tRNA
  9. Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect
  10. Post-transcriptional modifications to tRNA - A response to the genetic code degeneracy
  11. Biochemical characterization of pathogenic mutations in human mitochondrial methionyl-tRNA formyltransferase
  12. A Divalent Metal Ion-Dependent N1-Methyl Transfer to G37-tRNA
  13. A dual-targeted aminoacyl-tRNA synthetase in Plasmodium falciparum charges cytosolic and apicoplast tRNACys
  14. Amino acid - Dependent stability of the acyl linkage in aminoacyl-tRNA
  15. The selective tRNA aminoacylation mechanism based on a single G.U pair
  16. Impaired function is a common feature of neuropathy-associated glycyl-tRNA synthetase mutations
  17. A Recurrent Loss-of-Function Alanyl-tRNA Synthetase (AARS) Mutation in Patients with Charcot-Marie-Tooth Disease Type 2N (CMT2N)
  18. Structural and mechanistic basis for enhanced translational efficiency by 2-thiouridine at the tRNA anticodon wobble position
  19. The temperature sensitivity of a mutation in the essential tRNA modification enzyme tRNA methyltransferase D (TrmD)
  20. Conservation of structure and mechanism by Trm5 enzymes