Haiwei SONG  
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  Haiwei SONG  
  Lab Location: #7-14

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  Key Publications  

Ren W, Chen H, Sun Q, Tang X, Huang J, Song H* (2014)
Structural Basis of SOSS1 Complex Assembly and Recognition of ssDNA.
Cell Rep.
6, 982-91.
Wu D, Muhlrad D, Bowler MW, Liu Z, Parker R, Song H (2014) Lsm2 and Lsm3 bridge the interaction of the Lsm1-7 complex with Pat1 for decapping activation. Cell Res. 24, 233-46.

Fan H, Dong Y, Wu D, Bowler MW, Zhang L, Song H (2013) QsIA disrupts LasR dimerization in antiactivation of bacterial quorum sensing. Proc Natl Acad Sci U S A. 110, 20765-70.

Lai T, Cho H, Liu Z, Bowler MW, Piao S, Parker R, Kim YK, Song H (2012)
Structural Basis of the PNRC2-Mediated Link between mRNA Surveillance and Decapping
Structure  20, 2025-37.

Lim SC, Bowler MW, Lai TF, Song H (2012).
The Ighmbp2 helicase structure reveals the molecular basis for disease-causing mutations in DMSA1.
Nucleic Acids Res. 40,11009-22.

Chen L, Muhlrad D, Hauryliuk V, Cheng  Z, Lim MK, Shyp V, Parker R and Song H (2010) Structure of the Dom34-Hbs1 Complex and implications for No-Go decay. 
Nat. Struct. & Mol. Biol. 17, 1233-40.

Chen L, Chan SW, Zhang  X, Walsh M, Lim CJ, Hong W  and Song  H (2010)
Structural basis of YAP recognition by TEAD4 in the Hippo pathway
Genes & Development, 24, 290-300.

Cheng Z, Saito K, Pisarev AV, Wada M, Pisareva VP, Pestova TV, Gajda M, Round A, Kong C, Lim M, Nakamura Y, Svergun DI, Ito K, Song H. (2009).
Structural insights into eRF3 and stop codon recognition by eRF1. 
Genes &
Development 23, 1106-1118.

She, M, Decker CJ, Svergun DI, Round A, Chen N, Muhlrad D, Parker R, Song H (2008). Structural basis of Dcp2 recognition and activation by Dcp1. 
Mol. Cell 29, 337-349.

Gao, H.,  Zhou, Z., Rawat, U., Huang, C., Bouakaz, L., Wang, C., Cheng, Z., Liu, Y., Zavialov, A., Gursky, R., Sanyal, S., Ehrenberg, M., Frank, J. and Song H.  (2007). RF3 Induces ribosomal conformational changes responsible for the dissociation of class-I release factor.
Cell  129, 929-941.

Cheng, Z.,  Muhlrad, D., Lim, M. K., Parker R. and Song H. (2007).
Structural and functional insights into the human Upf1 helicase core.  EMBO J26, 253-264.

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  Haiwei SONG

Haiwei SONG received his BSc (1987) in Chemistry from Henan University, MSc (1990) in Molecular Biology from the Institute of Biophysics, China and PhD (1998) in Molecular Biology in Leeds University, UK. He worked as a Postdoctoral Research Associate in the Laboratory of Molecular Biophysics in Oxford University and Institute of Cancer Research in London before he joined the ex-Institute of Molecular Agrobiology in Singapore as a Principal Investigator in 2001. He moved to IMCB in 2002 and is currently a Research Director/Professor.

  Medical Structural biology

Dr. Song’s laboratory is interested in studying structure and function of proteins and complexes implicated in human diseases such as genetic and neurological disorders as well as cancers. His current research aims to determine the structures of proteins involved in RNA metabolism and human diseases and proteins involved in the Hippo signaling pathway. 

RNA metabolism and human diseases
Multiple cellular functions and pathways are controlled by protein-coding, non-coding RNAs and the RNA-binding proteins associated with them, which form the ribonucleoprotein complexes (RNPs). Mutations that disrupt the functions of RNAs and RNPs are the underlying cause of numerous human diseases. The study of RNA metabolism offers many new opportunities for novel diagnostic and therapeutic intervention. 

(1) Nonsense-mediated mRNA decay

Nonsense-mediated mRNA decay (NMD) is an mRNA surveillance mechanism that recognizes and degrades aberrant mRNAs that have acquired premature translation termination codons due to failure in mRNA processing or genetic mutation. There are around 200 human genetic diseases that result from the premature translation termination. Studies of the proteins required for NMD may lead to rational approaches for the treatment of these genetic disorders. An important step in NMD is the translation-dependent recognition of transcripts with aberrant termination events and then targeting those mRNAs for destruction. In NMD, mRNAs with premature termination codons are degraded either by deadenylation-independent decapping (5'-3' NMD) or by accelerated deadenylation (3'-5' NMD) pathways. The NMD pathway depends on a set of three conserved proteins Upf1, Upf2 and Upf3 that modulate both transcript stability and translation termination efficiency. The key member of this protein set is Upf1, which recognizes aberrant translation termination events by interacting with release factors eRF1 and eRF3, and then in a subsequent step, interacts with Upf2 and Upf3 to trigger degradation of mRNA. We have determined the crystal structure of the catalytic core of human Upf1. Our future goal is to determine the crystal structure of eRF1/eRF3/Upf1 to understand the molecular basis of interplay between premature translation termination and NMD.

(2) Distal Spinal Muscular Atrophy type 1 (DSMA1)

Distal spinal muscular atrophy type 1 (DSMA1) is an autosomal recessive disorder resulting from the degeneration of α-motoneurons in the spinal cord. It manifests itself in early childhood and is characterized by early respiratory failure due to diaphragmatic paralysis. DSMA1 is caused by genetic mutations in the Ighmbp2 gene, which encodes immunoglobulin µ-binding protein 2 (Ighmbp2). The precise cellular function of Ighmbp2 remains elusive, although it has been implicated in transcription and pre-mRNA processing and more recently has been functionally linked to translation. Ighmbp2 is a multidomain protein composed of a DNA/RNA-helicase domain and an R3H domain and a zinc-finger domain and belongs to a subfamily of the Upf1-like group within the helicase superfamily 1 (SF1). We have solved the crystal structures of the Ighmbp2 helicase core with and without bound RNA. Mapping of the pathogenic mutations of DSMA1 onto the helicase core structure provides a molecular basis for understanding the disease causing consequences of Ighmbp2 mutations.

    Fig.1 Mapping of the pathogenic mutations of DSMA1 onto the helicase core structure of Ighmbp2

(3) Long Noncoding RNAs (lncRNAs)

Long noncoding RNAs (lncRNA) are transcribed RNA molecules greater than 200 nucleotides in length. lncRNAs function as signal, decoy, guide and scaffold in the basal regulation of protein-coding genes central to development and oncogenesis at both transcriptional (e.g. epigenetic) and post-transcriptional levels. The dysregulation of lncRNAs has been associated with many complex human diseases, including leukaemia, colon cancer, prostate cancer, breast cancer, hepatocellular carcinoma, psoriasis, ischaemic heart disease, Alzheimer's disease and spinocerebellar ataxia type 8. The most dominant function explored in lncRNA studies relates to epigenetic regulation of target genes. The lncRNA HOTAIR target and direct chromatin-modifying complexes to their target genes while the lncRNA Xist interacts with a specific transcription factor to form a molecular bridge to connect this transcription factor and a chromatin-modifying complex in order to repress genes on the inactive chromosome. HOTAIR directs the action of polycomb chromatin remodeling complexes in trans to govern the cells' epigenetic state and subsequent gene expression. HOTAIR has two main functional domains, a polycomb PRC2-binding domain at its 5' end and an LSD1/CoREST1-binding domain at its 3' end, therefore acting as a scaffold to link two repressive protein complexes for coordinating their function. We seek to understand the structural basis of HOTAIR-mediated epigenetic regulation by determining the crystal structure of HOTAIR in complex with the PRC2 complex or the LSD1 complex.

The Hippo signaling pathway and tumorigenesis

The Hippo signaling pathway controls cell growth, proliferation, and apoptosis by regulating the expression of target genes that execute these processes. While there are multiple proteins involved in the pathway, they can be grouped into three components: the upstream regulatory factors, the kinase core and the downstream transcriptional machinery wherein YAP functions as a transcriptional co-activator by interacting with the conserved TEAD family transcription factors. YAP mediates the output of Hippo pathway including growth control and cancer development. The abnormal activation of YAP has been associated with multiple types of cancer.  We have solved the crystal structure of YAP in complex with TEAD4. These results provide mechanistic insights into the structural basis of YAP/TEAD interaction and also offer a new strategy for cancer therapeutics by disrupting the YAP/TEAD interaction. We will continue our efforts in elucidating the structures of proteins/complexes involved in this pathway including the key kinase complexes MST1/SAV1 and LATS1/Mob as well as the Axl receptor tyrosince kinase. Axl is a critical mediator of YAP-dependent oncogenic activities and is a potential therapeutic target for Hepatocellular carcinoma. Axl has also been implicated in pancreatic carcinoma, human gliomas, breast cancer and acute leukemia. Small molecular inhibitors of Axl have emerged and are in various stages of drug development. However, no compounds specifically designed to target Axl are in the clinical stages of development due to the lack of its structural information. We will determine the crystal structure of the kinase domain of Axl in apo form and in complex with the known inhibitors.

    Fig. 2 Crystal structure of TEAD4 (green) with bound YAP peptide (pink) showing three interaction sites.