Identification of the molecular defect in factor IX Chapel Hill: substitution of histidine for arginine at position 145.
Identification of the molecular defect in factor IX Chapel Hill: substitution of histidine for arginine at position 145.
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Chapel Hill IX 因子分子缺陷的鉴定：用组氨酸替代第 145 位的精氨酸。
DOI：
10.1073/pnas.80.14.4200
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发表时间：
1983
影响因子：
11.1
通讯作者：
R. Lundblad
中科院分区：
文献类型：
--
作者：
C. Noyes;M. Griffith;H. Roberts;R. Lundblad
血友病B查佩尔山是一种轻度遗传性出血性疾病，其中因子IX抗原以正常量存在，但因子IX生物活性显著降低。以前的研究已经证明，纯化的因子IX查佩尔山具有正常人因子IX活性的8%，并且因子IX查佩尔山的活化是有缺陷的，因为在正常因子IX的活化过程中水解的两个肽键中只有一个被切割。通过高效液相色谱法对来自正常人因子IX和因子IX查佩尔山的胰蛋白酶肽进行分析。从因子IX查佩尔山和正常因子IX获得的肽的洗脱曲线的比较表明，来自正常分子的三肽Leu-Thr-Arg（位置143-145）紧接在145-146处的Arg-Ala肽键的氨基末端，所述Arg-Ala肽键在用因子XIa活化因子IX期间被切割，在从因子IX查佩尔山获得的消化物中不存在。通过进一步的高效液相色谱分离获得来自因子IX查佩尔山的延长的“活化肽”，并进行一级结构分析。获得对应于位置143-147的以下序列：Leu-Thr-His-Ala-Glu。因此，因子IX查佩尔山中的主要分子缺陷是组氨酸取代了145位的精氨酸。该取代排除了因子XIa在该肽键处的裂解，并且活化肽区域保持与因子IXa的轻链结合查佩尔山。
Hemophilia B Chapel Hill is a mild hereditary hemorrhagic disorder in which the factor IX antigen is present in normal amounts but factor IX biological activity is markedly reduced. Previous studies have demonstrated that purified factor IX Chapel Hill has 8% of the activity of normal human factor IX and that the activation of factor IX Chapel Hill is defective in that only one of the two peptide bonds hydrolyzed during activation of normal factor IX is cleaved. The tryptic peptides from normal human factor IX and factor IX Chapel Hill were subjected to analysis by high-performance liquid chromatography. Comparison of the elution profile of the peptides obtained from factor IX Chapel Hill and normal factor IX demonstrated that the tripeptide Leu-Thr-Arg, which is derived from the normal molecule (positions 143-145) immediately amino-terminal from the Arg-Ala peptide bond at 145-146 that is cleaved during the activation of factor IX with factor XIa, was absent in the digest obtained from factor factor IX Chapel Hill. The elongated "activation peptide" from factor factor IX Chapel Hill was obtained by further high-performance liquid chromatographic fractionation and subjected to primary structure analysis. The following sequence, corresponding to positions 143-147, was obtained: Leu-Thr-His-Ala-Glu. Thus, the primary molecular defect in factor factor IX Chapel Hill is the substitution of histidine for arginine at position 145. This substitution precludes cleavage by factor XIa at this peptide bond, and the activation peptide region remains associated with the light chain of factor IXa Chapel Hill.