金黃色葡萄球菌 (Staphylococcus aureus) 屬於附生在人類表皮或是黏膜中常見的一種革蘭氏陽性 (Gram-positive) 共生菌。並且已經可以從一些文獻以及統計資料中得知目前金黃色葡萄球菌為醫院內感染 (nosocomial infections) 中最常見的原因。本研究中之SrrAB雙因子調控系統 (The staphylococcal respiratory response regulator SrrAB two component system, SrrAB TCS) 已經在現有的文獻中被證實到其會受到環境中氧含量的多寡而影響至下游基因的調控及表現，尤其是當其處在低氧的環境中時會去誘發下游ica基因座的轉錄和表現而增加多醣體 (polysaccharide) 的產生。當越來越多的多醣體產生時將會進一步的促使生物膜的形成，最終導致金黃色葡萄球菌能藉由生物膜的形成來抵抗抗生素以及逃避免疫系統的攻擊。SrrAB雙因子調控系統是由組胺酸激酶感應蛋白 (Sensor Histidine Kinase, HK) SrrB和反應調節蛋白(Response regulatory protein, RR) SrrA共同組成的。在本研究中則是先利用金黃色葡萄球菌的基因組DNA (genomic DNA) 來進行標的蛋白載體表現之構築，分別成功的構築出SrrB胞內區域 (dimeriation and ATPase domain of SrrB, SrrBc, residues 350-588) 和包含有SrrB中磷酸根接受區域 (dimeriation, ATPase domain and phosphoacceptor domain of SrrB, SrrBc2, residues 228-588) 以及全長之SrrB蛋白 (SrrB, 1-588胺基酸) 基因片段至pET-21a(+)表現載體中，之後再利用大腸桿菌表現系統順利的表達出SrrBc和SrrBc2以及SrrB全長之重組標的蛋白且在經由蛋白質純化後獲得具有高產量以及高純度之標的蛋白。最後則是對於標的蛋白進行蛋白質結晶條件篩選與晶體繞射數據收集，而在本研究中所收集到之SrrBc的蛋白質晶體繞射數據其最高的解析度可至1.78 Å，其空間群 (space group) 則是屬於單斜晶系的P21對稱，晶格 (unit cell) 參數為a＝61.13 Å, b＝58.17 Å, c＝70.29 Å並且在不對稱單元 (asymmetric unit) 中包含有兩個蛋白質分子所組合而成。其結構內包含有α螺旋 (α-helix) 所結合成的聚合區域 (dimerization domain) 和由α螺旋跟β摺板 (β-sheet) 組合而成的ATP激酶活化區域 (ATPase domain) 以及ATP-lid。最後根據已知的文獻結果以及在此所解析出的SrrBc晶體結構，我們在此提出了一個假說為存在於SrrBc晶體結構中的ATP激酶活化區域 (ATPase domain) 內含有一對雙硫鍵 (disulfide bond, 分別為Cys469和 Cys506) 會受到環境中的氧含量程度的影響而導致此雙硫鍵將會是處於在氧化 (oxidized) 或者是還原 (reduced) 的狀態，並藉此造成SrrBc的結構產生改變，最終影響至其與下游反應調節蛋白SrrA彼此間的交互作用並進一步的改變至下游基因的表現。

Staphylococcus aureus is a major cause of nosocomial infections today. S. aureus infection is considered to be the reason for the increasing number of antibiotic-resistant strains. Furthermore, S. aureus can persist in clinical settings and increase resistance to antimicrobial agents through biofilm formation. The staphylococcal respiratory response regulator SrrAB (synonym, SrhSR), a two-component system has been identified as a global regulator of the aerobic-anaerobic shift of metabolism in S. aureus. SrrB is a histidine kinase which responds to environmental stimuli by regulating its cognate response regulator SrrA. Under low-oxygen growth conditions, the staphylococcal regulator SrrAB induces ica locus transcription and polysaccharide intercellular adhesion (PIA) production, known as a major component of biofilm. Here, we report the crystal structure of cytoplasmic portion of SrrB (SrrBc, residues 350-588) from S. aureus in a dimeric form at 1.78 Å resolution. The crystals of SrrBc belong to the monoclinic space group P21, with unit-cell parameters a = 61.13 Å, b = 58.17 Å, c = 70.29 Å, β= 103.61∘, contain two protein molecules in the asymmetric unit. Moreover, we found that one disulfide bond (Cys469 and Cys506) is located within the core β-sheet to stable the structure. Finally, based on previous studies and our crystal structure, we propose that the redox state of this disulfide bond in the ATP binding domain of SrrB might play a key role to mediate the interaction between SrrB and SrrA, thus alter the target gene of SrrAB in transcription level in S. aureus.

吳彥宥 (2005) Xanthomonas campestris pv. Campestris 未知功能蛋白XC847的晶體結構及功能分析 (國立中央大學生命科學研究所碩士論文)

李玠姍 (2014) 金黃色葡萄球菌VraSR雙因子調控系統之功能與結構研究 (國立成功大學生物化學暨分子生物學研究所碩士論文)

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