I. Genome-wide identification of proteininteractome
Integrative systems biology
Protein-proteininteractions (PPIs) are crucial for many biological functions. Although
advances in high-throughput proteomics enable us to construct many
comprehensive PPI networks providing holistic view of biological phenomena,
there are huge amount of unidentified PPIs. Furthermore, little attention is
paid for the network-level understanding of diverse characteristics of PPI. We
attempt to solve these problems by integrating various approaches such as
modeling physical property of PPI, subcellular localization information, and
high-throughput genomics data. Following two subjects of biology are about PDZ domains and plasmamembrane proteins, in which you can discover insights that
cannot be unraveled in other ways.
PDZ domains: Interactions mediated by them and their global view
PDZ
domains play an important role on controlling the signal flow by assembling
multiple signaling components, such as enzymes, receptors, and ion channels.
The importance of understanding PDZ protein functions and interactions is
underscored by the fact that many PDZ domain-ligand interactions are related to
various diseases, including neurological disease and cancer. Therefore
revealing the PDZ domain-ligand interaction network lead us to elucidating
numerous cell signaling event and disease progression. Through a systematic
data integration, quantitative interaction modeling, and subcellular
localization mapping, we investigates the molecular mechanisms of various
signaling processes organized by PDZ proteins and evolutionary conservation of
PDZ domain-ligand interactions (Fig. 1A).
Plasmamembrane proteins: Both alternative expression
and partnering conduct their functional diversity
Cells can
respond to their environment by sensing signals and translating them into
changes in gene expression. Membrane proteins accept and transmit a variety of
extracellular signals so structural diversity is necessary to achieve
functional diversity. However, plasma membrane proteins happen to fall into
fewer families and folds compared to soluble proteins. Thus, we are trying to
answer the question that how functional diversity was achieved for plasma
membrane proteins by analyzing cellular interacting dynamics of plasma membrane
proteins (Fig. 1B).
Fig.1. Constructing protein interactome by integrating genome-wide datasets.
II. Systematic analysis of protein localizations in the cells
Protein
subcellular localization for disease profiling
Characterizing subcellular localizations of proteins provides a
key clue for understanding protein function. Many bioinformatics approaches
have focused on identifying protein subcellular localization using various
features from primary sequence. However, different programs often deliver
conflicting results regarding the localization of the same protein. Therefore,
we developed a consensus localization prediction method that is
based on a systematic integration of available programs and obtained
substantially high performance. Furthermore, with the high quality subcellular
localization information, we investigated the
relationship between disease-associated proteins and their subcellular
localizations (Fig. 2A).
Mitochondria biology
We focused on the mitochondria which are dynamic
organelles modulating various biological processes, such as metabolic
processes, energy production, and apoptosis through active communications with
other cellular compartments. Breakdown of the mitochondrial function often lead
to metabolic diseases. Recently, it has been studied that dysfunction of
mitochondria is related several common disease, such as diabetes and
nerodegeneration. Because most of mitochondrial proteins are encoded in the
nucleus, communication between mitochondria and nucleus is important to
maintain the dynamic properties of mitochondria. We integrate and manipulate
the high-throughput data, such as genomics, proteomics, and interactomics to
characterize novel mitochondrial proteins. Final goal of our lab is to find
mitochondrial disease gene candidates (Fig. 2B).
Fig.2. Identification of subcellular localizations of proteins
III. Evolutionary analysis protein structures and sequences
Bioinformatic approaches for the structure and function of
proteins
Proteins
are functional units to play important roles in the biology of the cell. While
the number of sequenced genomes continues to increase, experimentally verified
functional annotations and structures of whole genomes remains unknown. Because
subsequence experimental investigation is costly and time-consuming, accurate
computational methods for predicting protein functions and structures become attractive.
We develop various computational methods for identifying functionally important
residues and modeling structures by using evolutionary information.
Analyzing structural dynamics and function
Protein
sequence directly implies its structure that commands function. Protein
structure is dynamic and undergoes conformational changes which are fundamental
to control various biological processes such as cell signaling, gene
expression, and metabolic regulation. We are investigating the relationship
between conformational change and sequence evolution of proteins to understand
the mechanisms of protein conformational change and to identify the key
residues of structural transitions. Also, we are developing measurements to
identify functionally important residues of proteins. A newly derived
evolutionary feature, the integration score (IS), can capture the maximum
evolutionary property of functionally important cooperative residues that would
not be apparent by sequence conservation or co-evolution score
(Fig. 3A).
Also, we are developing algorithm
to identify binding interfaces of proteins by integrating evolutionary
information and computational docking. In protein docking, discriminating
near-native structures from artifacts generated by initial-stage docking is the
fundamental issue. We investigate a novel docking scoring methods solely based
on the basic principles of evolutionary conservation (Fig. 3B).
Characterizing fold space of membrane proteins
Membrane
proteins play important roles in many essential cellular processes and have
become attractive drug targets. Knowledge of the fold space of membrane
proteins can give valuable insights toward elucidating their structure and
function. Despite recent progresses of structural biology, the fold space of
membrane proteins still remains elusive due to difficulties in determining
high-resolution structures. We are trying to
understand the fold space of membrane proteins and its evolution through a
large-scale structural comparison of proteins (Fig. 3C).
Fig.3. Identification of functionally important sites and structures by using evolutionary information
