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. tRNA Methylation Is a Global Determinant of Bacterial Multi-drug Resistance
  2. Loss-of-function mutations in Lysyl-tRNA synthetase cause various leukoencephalopathy phenotypes
  3. Cysteinyl-tRNA Synthetase Mutations Cause a Multi-System, Recessive Disease That Includes Microcephaly, Developmental Delay, and Brittle Hair and Nails
  4. Codon-specific translation by m 1 G37 methylation of tRNA
  5. Erratum to: The selective tRNA aminoacylation mechanism based on a single G•U pair (Nature, (2014), 510, 7506, (507-511), 10.1038/nature13440)
  6. TRNA 3 -amino-tailing for stable amino acid attachment
  7. Hypermorphic and hypomorphic AARS alleles in patients with CMT2N expand clinical and molecular heterogeneities
  8. Compound heterozygosity for loss-of-function GARS variants results in a multisystem developmental syndrome that includes severe growth retardation
  9. Effect of Nascent Peptide Steric Bulk on Elongation Kinetics in the Ribosome Exit Tunnel
  10. A genetically encoded fluorescent tRNA is active in live-cell protein synthesis
  11. TrmD: A Methyl Transferase for tRNA Methylation With m 1 G37
  12. Transcription-Translation coupling: Direct interactions of RNA polymerase with ribosomes and ribosomal subunits
  13. Mg2+ regulates transcription of mgtA in Salmonella Typhimurium via translation of proline codons during synthesis of the MgtL peptide
  14. Initiator tRNA genes template the 3' CCA end at high frequencies in bacteria
  15. Methyl transfer by substrate signaling from a knotted protein fold
  16. Molecular basis and consequences of the cytochrome c-tRNA interaction
  17. A novel HSD17B10 mutation impairing the activities of the mitochondrial Rnase P complex causes X-linked intractable epilepsy and neurodevelopmental regression
  18. Kinetic Analysis of tRNA Methyltransferases
  19. Structural basis for methyl-donor-dependent and sequence-specific binding to tRNA substrates by knotted methyltransferase TrmD
  20. The UGG isoacceptor of tRNAPro is naturally prone to frameshifts