C1r酶 来源于正常人血清

C1r 酶是 C1r 酶原的活化形式。C1r 是 C1 复合物的一个亚基，而 C1 复合物是补体经典途径中的第一个补体成分。在 C1 被活化前，C1r 酶原是一种无活性的酶原。当 C1 与结合在抗原上的抗体（免疫复合物）结合并被其活化时，C1r 随之活化，生成 C1r 酶 —— 这是启动补体级联反应的第一种蛋白酶。C1 是由 1 个 C1q、2 个 C1r 和 2 个 C1s 分子构成的非共价结合钙依赖性复合物。每个 C1q 通过其 6 条臂中的两条或多条，与免疫球蛋白 G（IgG）或免疫球蛋白 M（IgM）的 Fc 结构域结合。多条臂与免疫复合物的结合，会使复合物中的两个 C1r 蛋白（蛋白酶原）活化，产生两种蛋白酶，这些蛋白酶会切割并活化复合物中的两个 C1s 蛋白酶原。C1r 的活化过程是通过自身裂解为分子量分别为 57,000 道尔顿和 35,000 道尔顿的两个片段实现的。C1r 酶唯一已知的功能是活化结合态的 C1s 分子。活化后的 C1s 会切割补体成分 C4，释放出 C4a，并启动 C4b 与活化表面的共价结合。此外，活化的 C1s 还会切割 C2，C2 裂解后产生的较大片段会与结合在表面的 C4b 结合，形成 C4bC2a—— 这是补体经典途径中的 C3/C5 转化酶。 消光系数 纯 C1r 在 1.0mg/ml 浓度下，280nm 处的吸光度（A280nm）为 1.15。 纯度：通过 SDS-PAGE（十二烷基硫酸钠 - 聚丙烯酰胺凝胶电泳）检测，纯度＞90%（注：非还原条件下，C1r 酶的分子量为 92,000 道尔顿；还原条件下，经 SDS-PAGE 检测，其会以 57,000 道尔顿和 35,000 道尔顿的两条链形式存在）。 防腐剂：无防腐剂，经 0.22μm 滤膜过滤。 来源：来源于正常人血清（经权威认证检测，乙型肝炎表面抗原（HBsAg）、人类 T 淋巴细胞白血病病毒 Ⅰ/Ⅱ 型（HTLV-Ⅰ/Ⅱ）、梅毒血清学检测（STS）均呈阴性，且丙型肝炎病毒（HCV）抗体、人类免疫缺陷病毒 1 型（HIV-1）抗体及人类免疫缺陷病毒 2 型（HIV-2）抗体检测也均为阴性）。 注意事项：处理人类血液制品时，需采取常规防护措施。 物理特性与结构 C1r 酶是一种分子量为 92,000 道尔顿的双链胰蛋白酶样酶。血浆中 C1r 的浓度为 31μg/mL。C1r 酶原是一种不稳定的酶原，它会通过切割自身的一个肽键自发活化，生成分子量为 57,000 道尔顿的重链和 35,000 道尔顿的轻链，市售的 C1r 酶即为这种形式。在 C1 复合物与免疫复合物结合后，C1r 的这种自活化会迅速发生；而对于纯 C1r 而言，自活化过程则较为缓慢。在钙离子存在的条件下，两个 C1r 分子会形成 C1r-C1r 复合物，该复合物进而在钙离子存在时与两个 C1s 分子形成稳定复合物。 这种四聚体（C1r-C1r-C1s-C1s）可在溶液中存在，但在 C1q 存在的情况下，它会与 C1q 结合形成 C1 复合物，且该复合物在钙离子存在时保持稳定。当 C1r 处于 C1 复合物中时，其自活化会因与 C1 酯酶抑制剂（C1-INH）的弱结合而受到部分调控；纯化的 C1r 也会因类似的作用而保持稳定。然而，C1r 酶会通过与 C1-INH 结合而发生不可逆失活。 功能 C1r 酶可用于活化 C1s 酶原。在钙离子存在的条件下，C1r 酶仍能结合另一个 C1r 酶分子和两个 C1s 分子，且形成的复合物能够与 C1q 结合。活化后的 C1r 酶会迅速将两个 C1s 酶原活化为 C1s 酶，最终形成的 C1q-C1r₂-C1s₂复合物是完全活化的 C1 分子，该分子可在液相中或在带有抗体的细胞（如 EA 细胞）表面活化 C4 和 C2。其中，EA 细胞是指表面结合了兔抗绵羊红细胞 IgM 抗体的绵羊红细胞。 检测方法 C1r 酶的活性可通过以下方式检测：测定其与蛋白酶抑制剂（C1 酯酶抑制剂）的结合能力，以及在 SDS 存在条件下保持共价结合的能力。此外，也可通过检测其活化 C1s 酶原、形成由 1 个 C1q、2 个 C1r 和 2 个 C1s 分子构成的活化 C1 复合物的能力来判断其活性。 应用领域 详见上文 “功能” 与 “检测方法” 部分。 调控机制 活化的 C1r 会被 C1-INH 迅速灭活。对于纯 C1 复合物和纯 C1r 酶原而言，其观察到的 C1r 自发活化现象会因 C1-INH 的存在而减弱 —— 因为 C1-INH 会快速灭活自发活化的 C1r 酶。C1r 酶原的稳定性还源于其与 C1-INH 形成的弱复合物：这种结合显然能稳定 C1 的结构，从而防止其在血清中发生自发活化。在纯化过程中，C1-INH 与 C1 的分离是导致分离得到的 C1 复合物和 C1r 酶原不稳定、易发生自发活化的原因之一。 遗传学信息 C1r 的 EMBL/GenBank cDNA 登录号为 M14058。C1r 基因与 C1s 基因紧密连锁，且均定位于 12 号染色体短臂 1 区 3 带（12p13）。 缺陷相关 目前已发现 C1 复合物的三个组成成分（C1q、C1r、C1s）均存在缺陷情况。其中，C1r 或 C1s 缺陷的患者易患系统性红斑狼疮（SLE）和复发性化脓性感染。这类患者缺乏补体经典途径的功能，其血液中可能检测到 C1r 抗原，也可能检测不到。 相关疾病 详见上文 “缺陷相关” 部分。 注意事项 / 毒性 / 危害 该蛋白质从人血清中纯化获得，因此，即使来源血清经权威认证检测显示乙型肝炎表面抗原（HBsAg）、人类 T 淋巴细胞白血病病毒 Ⅰ/Ⅱ 型（HTLV-Ⅰ/Ⅱ）、梅毒血清学检测（STS）均呈阴性，且丙型肝炎病毒（HCV）抗体、人类免疫缺陷病毒 1 型（HIV-1）抗体及人类免疫缺陷病毒 2 型（HIV-2）抗体检测也均为阴性，处理时仍需采取适用于所有血液衍生制品的防护措施。 C1r enzyme is the activated form of C1r proenzyme. C1r is a subunit of the C1 complex which is the first complement component in the classical pathway of complement. C1r proenzyme is an inactive zymogen until C1 is activated. C1r is activated when C1 binds to and is activated by antibodies bound to antigens (immune complexes) yielding C1r enzyme, the first protease that initiates the cascade. C1 is a non-covalent calcium-dependent complex of one C1q, two C1r and two C1s molecules. Each C1q binds through two or more of its six arms to the Fc domains of IgG or IgM. The binding of multiple arms to immune complexes causes the two C1r proteins in the complex (protease zymogens) to activate producing two proteases that cleave and activate the two C1s protease zymogens in the complex. The activation of C1r results from cleavage of C1r into two fragments of 57,000 and 35,000 daltons. Activation of the bound C1s molecule is the only known function of C1r enzyme. Activated C1s cleaves complement component C4 releasing C4a and initiating covalent attachment of C4b to the activating surface. Activated C1s also cleaves C2 and the larger fragment of C2 binds to the surface-attached C4b forming C4b,C2a the C3/C5 convertase of the classical pathway. Extinction Coeff.: A280 nm = 1.15 at 1.0 mg/ml for pure C1r Purity: >90 % by SDS PAGE (Note: C1r enzyme is 92,000 unreduced, but upon reduction runs as 57,000 and 35,000 chains on SDS PAGE) Preservative: None, 0.22 µm filtered. Source: Normal human serum (shown by certified tests to be negative for HBsAg, HTLV-I/II, STS, and for antibodies to HCV, HIV-1 and HIV-II). Precautions: Use normal precautions for handling human blood products. Physical Characteristics & Structure C1r enzyme is a 92,000 dalton, two chain, trypsin-like enzyme. C1r is present in plasma at 31 μg/mL. C1r proenzyme is an unstable zymogen and it spontaneously activates by cleaving a peptide bond in C1r producing a 57,000 dalton heavy chain and a 35,000 dalton light chain. This is the form sold as C1r enzyme. This self-activation occurs rapidly in the C1 complex upon binding to an immune complex and it occurs slowly with pure C1r. Two C1r form a C1r-C1r complex in the presence of calcium which in turn forms a stable complex with two C1s molecules in the presence of calcium. This tetramer can exist in solution, but in the presence of C1q it binds to C1q forming the C1 complex, which is stable in the presence of calcium. C1r self-activation is controlled in part by a weak association with C1esterase inhibitor (C1-INH) when it is in the C1 complex and similar stabilization occurs with purified C1r. C1r enzyme, however, is irreversibly inactivated by binding to C1-INH. Function C1r enzyme can be used to activate C1s proenzyme. In the presence of calcium it is still capable of binding another C1r enzyme and two C1s molecules and this complex is capable of binding to C1q. The activated C1r enzyme will rapidly activate the two C1s proenzymes to form C1s enzymes and the resulting C1q-C1r2-C1s2 complex is a fully active C1 molecule which will activate C4 and C2 in the fluid phase or on a cell bearing antibodies, such as EA. EA are sheep erythrocytes with rabbit IgM anti-sheep erythrocytes antibodies bound to their surface. Assays The activity of C1r enzyme is checked by measuring its ability to bind to the protease inhibitor C1 esterase inhibitor and remain covalently bound in the presence of SDS. It may also be used to activate C1s proenzyme and to form the activated C1 complex composed of one C1q, two C1r and two C1s molecules. Applications See sections titled Function and Assays above. Regulation Activated C1r is rapidly inactivated by C1-INH . The spontaneous activation of C1r observed with pure C1 and pure C1r proenzyme is minimized by the presence of C1-INH which rapidly inactivates spontaneously activated C1r enzyme. Stabilization of the proenzyme is also due to existence of a weak complex between C1-INH and C1r proenzyme. This association apparently stabilizes C1 thus preventing spontaneous activation in serum. Separation of C1-INH from C1 during purification is one of the reasons that isolated C1 and C1r proenzyme is unstable and prone to spontaneous activation. Genetics The EMBL/Genbank cDNA accession number for C1r is M14058. The genes for C1r and C1s are closely linked and located on chromosome 12p13. Deficiencies Deficiencies of each of the three components of C1 have been found. C1r and C1s deficient patients are prone to systemic lupus erythematosus (SLE). and recurrent pyogenic infections. They lack classical pathway function and may or may not exhibit C1r antigen in blood. Diseases See section titled Deficiencies above. Precautions/Toxicity/Hazards This protein is purified from human serum and therefore precautions appropriate for handling any blood-derived product must be used even though the source was shown by certified tests to be negative for HBsAg, HTLV-I/II, STS, and for antibodies to HCV, HIV-1 and HIV-II.

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