Scheduled Seminars on 6/24/2014

Dapeng Zhang at 11:00  Edit  Reschedule  Delete

Uncovering molecular foundations of diseases by using domain-centric strategies
A significant contribution of recent biomedical research to human diseases is that many genes/biomarkers (and their specific mutations) have been identified as strongly associated with certain diseases by using biochemical, genetic or high-throughput screenings. However, the detailed molecular mechanisms underlying the pathology of these genes/their mutations often remain unclear. In this presentation, I will use two example studies to illustrate how domain-centric analyses can contribute to understanding the role of specific biomarkers in the etiology of their associated diseases.

First I will focus on ciliopathies, a collection of diseases unified by defects in human cilia structure which include Nephronophthisis (NPHP), Meckel-Gruber syndrome (MKS), and Bardet-Biedl syndrome (BBS). By systemically studying over 200 ciliopathy-related proteins, I have characterized novel functional domain components and for the first time establish that many bear two functional themes: peptidase activity defined by three distinct members of the transglutaminase-like peptidase fold and membrane localization activity defined by over 12 novel C2 domains. These results not only provide molecular insights into the reconstruction of the ciliary transitional zone, but also reveal that ciliopathies, although arising from disruptions of different genes, share a common mechanistic basis related to membrane interactions.

Second, I will focus on neurodevelopmental and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD). Recently, a mutation in the hypothetical gene C9ORF72 was identified as the crucial common genetic marker for these conditions. I show that C9ORF72, as a novel version of the DENN protein, is a GDP-GTP exchange factor (GEF) for Rab GTPases, which are regulators of practically all membrane trafficking events in eukaryotes. This suggests that defects in specific Rab-dependent vesicular trafficking processes could play a significant role in ALS and FTD. By identifying other distant versions of DENN proteins, I further show that common membrane trafficking defects also underlie distinct diseases like Birt-Hogg-Dubé syndrome (FLCN) and Smith-Magenis syndrome (SMCR8).

Altogether, these studies illustrate that the functional dissection of protein domain components is a robust strategy to understand the molecular foundations of human diseases.


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