Page 52 - Biennial Report 2018-20 Jun 2021

To evaluate the moderation effects of socio-economic status on air pollution induced low lung
function, lung function was measured in about 550 subjects living in areas with varying degrees
of air quality and varying socio-economic profiles. It was found that underprivileged people like
e rickshaw drivers exposed to traffic pollution were the worst affected, followed by industrial
pollution exposed people from Meerut. Subjects living near landfills and dumpsites were not
very different from people living in Delhi, but have relatively low lung function compared to the
Delhi population with better socio-economic backgrounds.

ACCURATE DETERMINATION OF STRUCTURAL MODULATION UNDERLYING
FUNCTIONAL DIVERSITY OF LC3 FAMILY MEMBERS

Autophagy is a key cellular degradation mechanism in nearly all organisms. Core components of
this machinery are the six human Atg8 orthologs that play a critical role in autophagosome
initiation and expansion. Although LC3B labeling is perhaps the most well-established and
representative marker for autophagy, the ambiguity regarding its evolutionary partners (LC3A,
LC3C, GABARAP, GABRAPL1, and GATE16) and their binding specificities is striking. In part, the
difficulty in constructing functional signatures arises due to remarkable structural similarity as
all of them share ubiquitin fold. The open question was how specific sequence variation amongst
the family members lead to different substrate recognition preferences.
To understand this, Thukral group developed a computational pipeline to define structural
determinants of human Atg8 family members that dictate functional diversity. They observed a
clear evolutionary separation between Atg8 orthologs and defined novel sequence recognition
motif for human LC3 and GABARAP subfamilies. By analyzing molecular dynamics (MD)
trajectories of known protein structures, it was observed that functional modules or
microclusters reveal a pattern of intramolecular network, including distinct hydrogen bonding of
key residues that may directly modulate their interaction preferences.

Lipi Thukral’s group routinely leverages high-throughput molecular dynamics simulations to
achieve conformational ensemble of proteins and other biomolecules. In this work, they
performed multiple simulations to characterize how six autophagy proteins interact with a
common protein binding partner, PLEKHM1. Their analysis showed remarkable differences in
binding modes via intrinsic protein dynamics, with PLEKHM1-bound GABARAP complexes
showing less fluctuations and higher number of contacts. Further, they could demonstrate that
distinct cancer-related mutations were likely to lead to significant structural changes. These
findings provide an extensive structural framework of diversity within human ATG8 proteins they
may serve as an underlying mechanism of crosstalk and molecular control with other related
signaling pathways.

GEAR – GENOMIC, EVOLUTIONARY AND BIG DATA ANALYTIC STRATEGIES TO
ADDRESS ANTIMICROBIAL RESISTANCE

Advancements in genome sequencing projects have made available thousands of phenotype
associated genomes of microbes, especially treated with specific antibiotics. The available

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