BACKGROUND The ubiquitous non-receptor protein tyrosine phosphatase SHP2 (encoded by PTPN11) plays a key role in RAS/ERK signaling downstream of most, if not all growth factors, cytokines and integrins, although its major substrates remain controversial. Mutations in PTPN11 lead to several distinct human diseases. Germ-line PTPN11 mutations cause about 50% of Noonan Syndrome (NS), which is among the most common autosomal dominant disorders. LEOPARD Syndrome (LS) is an acronym for its major syndromic manifestations: multiple Lentigines, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of genitalia, Retardation of growth, and sensorineural Deafness. Frequently, LS patients have hypertrophic cardiomyopathy, and they might also have an increased risk of neuroblastoma (NS) and acute myeloid leukemia (AML). Consistent with the distinct pathogenesis of NS and LS, different types of PTPN11 mutations cause these disorders. RESULTS Although multiple studies have reported the biochemical and biological consequences of NS- and LS-associated PTPN11 mutations, their structural consequences have not been analyzed fully. Here we report the crystal structures of WT SHP2 and five NS/LS-associated SHP2 mutants. These findings enable direct structural comparisons of the local conformational changes caused by each mutation. CONCLUSIONS Our structural analysis agrees with, and provides additional mechanistic insight into, the previously reported catalytic properties of these mutants. The results of our research provide new information regarding the structure-function relationship of this medically important target, and should serve as a solid foundation for structure-based drug discovery programs.

中文翻译：

---

对 Noonan/LEOPARD 综合征相关蛋白酪氨酸磷酸酶 SHP2 (PTPN11) 突变体的结构见解。

背景普遍存在的非受体蛋白酪氨酸磷酸酶 SHP2（由 PTPN11 编码）在大多数（如果不是全部）生长因子、细胞因子和整合素的下游 RAS/ERK 信号传导中起关键作用，尽管其主要底物仍然存在争议。PTPN11 中的突变会导致几种不同的人类疾病。生殖系 PTPN11 突变导致约 50% 的努南综合征 (NS)，这是最常见的常染色体显性遗传疾病之一。LEOPARD 综合征 (LS) 是其主要综合征表现的首字母缩写词：多发性扁桃体、心电图异常、眼距过宽、肺动脉狭窄、生殖器异常、生长迟缓和感音神经性耳聋。通常，LS 患者患有肥厚型心肌病，而且他们患神经母细胞瘤 (NS) 和急性髓系白血病 (AML) 的风险也可能增加。与 NS 和 LS 的不同发病机制一致，不同类型的 PTPN11 突变会导致这些疾病。结果 尽管多项研究报告了 NS 和 LS 相关 PTPN11 突变的生化和生物学后果，但尚未充分分析其结构后果。在这里，我们报告了 WT SHP2 和五个 NS/LS 相关 SHP2 突变体的晶体结构。这些发现能够对由每个突变引起的局部构象变化进行直接的结构比较。结论我们的结构分析与先前报道的这些突变体的催化特性一致，并提供了额外的机制洞察力。我们的研究结果提供了有关这一医学上重要目标的结构 - 功能关系的新信息，