Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg 69117, Germany.
Collaboration for joint PhD degree between EMBL and Heidelberg University, Faculty of Biosciences.
Sci Signal. 2021 Jan 12;14(665):eabd0334. doi: 10.1126/scisignal.abd0334.
The first reported receptor for SARS-CoV-2 on host cells was the angiotensin-converting enzyme 2 (ACE2). However, the viral spike protein also has an RGD motif, suggesting that cell surface integrins may be co-receptors. We examined the sequences of ACE2 and integrins with the Eukaryotic Linear Motif (ELM) resource and identified candidate short linear motifs (SLiMs) in their short, unstructured, cytosolic tails with potential roles in endocytosis, membrane dynamics, autophagy, cytoskeleton, and cell signaling. These SLiM candidates are highly conserved in vertebrates and may interact with the μ2 subunit of the endocytosis-associated AP2 adaptor complex, as well as with various protein domains (namely, I-BAR, LC3, PDZ, PTB, and SH2) found in human signaling and regulatory proteins. Several motifs overlap in the tail sequences, suggesting that they may act as molecular switches, such as in response to tyrosine phosphorylation status. Candidate LC3-interacting region (LIR) motifs are present in the tails of integrin β and ACE2, suggesting that these proteins could directly recruit autophagy components. Our findings identify several molecular links and testable hypotheses that could uncover mechanisms of SARS-CoV-2 attachment, entry, and replication against which it may be possible to develop host-directed therapies that dampen viral infection and disease progression. Several of these SLiMs have now been validated to mediate the predicted peptide interactions.
宿主细胞上首个被报道的 SARS-CoV-2 受体是血管紧张素转化酶 2（ACE2）。然而，病毒刺突蛋白也具有 RGD 基序，提示细胞表面整合素可能是共受体。我们利用真核线性基序（ELM）资源，对 ACE2 和整合素的序列进行了研究，在其无规则的短胞质尾部中鉴定到具有潜在的内吞作用、膜动力学、自噬、细胞骨架和细胞信号作用的候选短线性基序（SLiM）。这些 SLiM 候选物在脊椎动物中高度保守，可能与内吞作用相关的 AP2 衔接子复合物的 μ2 亚基以及人类信号和调节蛋白中存在的各种蛋白结构域（即 I-BAR、LC3、PDZ、PTB 和 SH2）相互作用。尾部序列中的几个基序重叠，提示它们可能作为分子开关，例如对酪氨酸磷酸化状态做出响应。候选 LC3 相互作用区域（LIR）基序存在于整合素β和 ACE2 的尾部，表明这些蛋白可以直接募集自噬成分。我们的发现确定了几个分子联系和可测试的假说，这些假说可能揭示 SARS-CoV-2 附着、进入和复制的机制，从而有可能开发针对宿主的治疗方法，抑制病毒感染和疾病进展。目前已经验证了其中的几个 SLiM 来介导预测的肽相互作用。
