호모올리고 효소단백질의 유연성과 신호전달

학위논문(석사) - 한국과학기술원 : 바이오및뇌공학과, 2009.2, [ vi, 45 p. ]In a cell, enzymes dynamically regulate all types of cell metabolism. It is known that enzymes are often in a homo-oligomeric state. Dynamic flexibility of catalytic sites, as well as efficient signal propagation between them, is critical for a protein to function properly. However, it is difficult, if not impossible, to study the protein dynamics using conventional all-atom molecular dynamics (MD) simulation method because it requires a prohibitively long simulation time. This difficulty is more severe for the oligomeric proteins because of their large size and relatively slow dynamics. Fortunately, however, simplified dynamics tools are emerging in recent years. One of the popular methods is the Gaussian network model (GNM), which successfully describes protein equilibrium dynamics by modeling a protein structure as a collection of the harmonically coupled residues. By using GNM, collective normal modes of protein can be easily calculated regardless of the size of proteins, from which information relevant to protein function such as dynamic flexibility of residues and the signal propagation between residues can be extracted. In this paper, we studied how oligomerization influences We first studied the dynamic flexibility of catalytic sites in homo-oligomer enzymes. We found that these flexibilities are closely related with the number of subunits and the structural stability of homo-oligomer enzymes. And then, we calculated the signal propagation between catalytic sites in the different domain in homo-oligomer enzymes. Our results indicate that these signals depend on physical distances between them and the oligomeric configurations; if two catalytic sites was close, then the signal is slow, and vice versa.한국과학기술원 : 바이오및뇌공학과

Different Characteristics of Childhood Asthma Related to Polyhexamethylene Guanidine Exposure

Rationale: Exposure to humidifier disinfectants (HDs) can increase the risk of asthma, but the characteristics of HD-related asthma are currently unclear. Polyhexamethylene guanidine (PHMG)-containing HD was the most commonly used and the most frequently associated with HD-associated lung injury. Objectives: To investigate the characteristics of PHMG-induced asthma. Methods: This general population-based birth cohort study used data from the Panel Study of Korean Children from 2008 (n = 846). Spirometry, bronchial provocation tests, detailed history recording, and physical examinations were performed on 7-year-old patients (n = 362). Exploratory analysis of plasma proteomics was performed. Results: Compared with the healthy control group, forced expiratory volume in 1 second was the lowest in PHMG-exposed asthma group (z-score = 20.806; 95% confidence interval, 21.492 to 20.119). The positive rate of bronchial hyperresponsiveness was lower in children with PHMG-exposed asthma compared with children with asthma without HD exposure (13.3% vs. 47.4%). Long-term exposure to low-intensity PHMG before the age of 3 years was associated with asthma symptoms. Periostin was higher in subjects with asthma without HD exposure compared with the healthy control subjects. The inducible T-cell costimulator ligand and hepatocyte growth factor activator were lower in PHMG-exposed asthma compared with asthma without exposure. Hepatocyte growth factor activator had a positive correlation with forced vital capacity (z-score) in asthma with PHMG exposure (r = 0.78; P < 0.01). Conclusions: The asthma associated with low-intensity exposure to PHMG is characterized by lower lung function, lower positive rates of bronchial hyperresponsiveness, and varied distributions of plasma proteins. These findings suggest that asthma related to PHMG exposure may constitute a different mechanism of asthma pathophysiology

Plasma Proteome Signature to Predict the Outcome of Breast Cancer Patients Receiving Neoadjuvant Chemotherapy

Abstract The plasma proteome of 51 non-metastatic breast cancer patients receiving neoadjuvant chemotherapy (NCT) was prospectively analyzed by high-resolution mass spectrometry coupled with nano-flow liquid chromatography using blood drawn at the time of diagnosis. Plasma proteins were identified as potential biomarkers, and their correlation with clinicopathological variables and survival outcomes was analyzed. Of 51 patients, 20 (39.2%) were HR+/HER2-, five (9.8%) were HR+/HER2+, five (9.8%) were HER2+, and 21 (41.2%) were triple-negative subtype. During a median follow-up of 52.0 months, there were 15 relapses (29.4%) and eight deaths (15.7%). Four potential biomarkers were identified among differentially expressed proteins: APOC3 had higher plasma concentrations in the pathological complete response (pCR) group, whereas MBL2, ENG, and P4HB were higher in the non-pCR group. Proteins statistically significantly associated with survival and capable of differentiating low- and high-risk groups were MBL2 and P4HB for disease-free survival, P4HB for overall survival, and MBL2 for distant metastasis-free survival (DMFS). In the multivariate analysis, only MBL2 was a consistent risk factor for DMFS (HR: 9.65, 95% CI 2.10-44.31). The results demonstrate that the proteomes from non-invasive sampling correlate with pCR and survival in breast cancer patients receiving NCT. Further investigation may clarify the role of these proteins in predicting prognosis and thus their therapeutic potential for the prevention of recurrence