Institute of Bioinformatics and Structural Biology
LIN LAB
1. Regulation of alternative splicing
​
Pre-mRNA splicing is a fundamental process for eukaryotic gene expression, and plays an extensive role in increasing protein diversity from a limited set of genes. It is carried out by the spliceosome, a large ribonucleoprotein (RNP) complex, which is made by stepwise assembly of five U-rich small nuclear RNPs (U1, U2, U4, U5, and U6 snRNP). Unlike unicellular eukaryotes, more than 95% of human genes undergo alternative splicing. It is therefore not surprising that aberrant splicing leads to numerous pathological disorders, including metabolic syndromes, cancer, cardiovascular diseases, and neurodegenerative disorders in human.
​
Recent development of single-particle cryo-EM has revealed the structures of spliceosomes in constitutive splicing. In the previous work, we unravelled the mechanism of authentic slice site recognition (Movie 1) and the formation of the active spliceosome (Figure 1) in yeast spliceosome. We next will focus on studying the modulatory effects of alternative splicing, a critical determinant of human genome complexity. The ultimate goal is to decipher the molecular basis of human diseases caused by dysregulated alternative splicing in order to set the stage for developing novel therapeutics through controlling the alternative splicing factors.
Movie 1. The cryo-EM structure of the yeast A complex.
​
Figure 1. The cryo-EM structure of the yeast B complex.
​
​
2. Structural studies of SMN-Gemins complex
​
Spinal muscular atrophy is an autosomal recessive neuromuscular disorder and the most common inherited fatal disease in infancy. It is caused by the deficiency of the SMN protein, a centre element of the SMN-Gemins complex which facilities the biogenesis of snRNPs (small nuclear RNPs). To understand the pathogenesis of spinal muscular atrophy and the molecular mechanism of snRNPs biogenesis, we aim to solve the cryo-EM structure of the SMN-Gemins complex and obtain structural snapshots of key intermediates at different steps of snRNP biogenesis.