Peptide ligands that use a novel binding site to target both TGF-β receptors.
Peptide ligands that use a novel binding site to target both TGF-β receptors.
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DOI：
10.1039/c0mb00115e
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发表时间：
2010-12
影响因子：
--
通讯作者：
Kiessling LL
中科院分区：
文献类型：
--
作者：
Li L;Orner BP;Huang T;Hinck AP;Kiessling LL
转化生长因子β（TGF-β）信号通路在发育和疾病中起着无数的作用。TGF-β亚型通过组织其细胞表面受体TβRI和TβRII启动信号传导。探索和利用TGF-β信号转导的多功能性需要增强对该途径中结构-功能关系的理解。为此，结合关键信号传导组分的小分子、肽和抗体效应物将充当有价值的探针。我们将TβRI-ED作为效应筛选的靶点。TβRI胞外区（TβRI-ED）可与TGF-β辅助受体（endoglin）结合，提示TβRI-ED可能具有多个相互作用位点。利用噬菌体展示技术，我们鉴定了两个与TβRI-ED结合的短肽LTGKNFPMFHRN（Pep 1）和MHRMPSFLPTTL（Pep 2）（Kd ~10-5 M）。虽然我们的筛选集中在TβRI-ED上，但命中肽与TβRII-ED以相似的亲和力相互作用。肽配体在TβRI和TβRII上占据相同的结合位点，如它们相互竞争受体结合的能力所证明的。此外，两者都不干扰TGF-β结合。这些结果表明，TβRI和TβRII都具有蛋白质-蛋白质相互作用的热点，这与其已知配体TGF-β所使用的热点不同。为了将这些化合物转化为高亲和力探针，我们利用了TβRI和TβRII在细胞表面以二聚体存在的观察结果;因此，我们组装了一个多价配体。具体来说，我们展示了我们的受体结合肽的树枝状支架。我们预期，所得到的有效多价配体可用于探测受体组装在TGF-β功能中的作用。
The transforming growth factor β (TGF-β) signaling pathway plays myriad roles in development and disease. TGF-β isoforms initiate signaling by organizing their cell surface receptors TβRI and TβRII. Exploration and exploitation of the versatility of TGF-β signaling requires enhanced understanding of structure–function relationships in this pathway. To this end, small molecule, peptide, and antibody effectors that bind key signaling components would serve as valuable probes. We focused on TβRI-ED as a target for effector screening. The observation that the extracellular domain of TβRI (TβRI-ED) can bind to a TGF-β coreceptor (endoglin), suggests that the TβRI-ED may have multiple interaction sites. Using phage display, we identified two peptides LTGKNFPMFHRN (Pep1) and MHRMPSFLPTTL (Pep2) that bind the TβRI-ED (Kd ~10-5 M). Although our screen focused on TβRI-ED, the hit peptides interact with the TβRII-ED with similar affinities. The peptide ligands occupy the same binding sites on TβRI and TβRII, as demonstrated by their ability to compete with each other for receptor binding. Moreover, neither interferes with TGF-β binding. These results indicate that TβRI and TβRII both possess hot spots for protein–protein interactions that are distinct from those used by their known ligand TGF-β. To convert these compounds into high affinity probes, we exploited the observation that TβRI and TβRII exist as dimers on the cell surface; therefore, we assembled a multivalent ligand. Specifically, we displayed one of our receptor-binding peptides on a dendrimer scaffold. We anticipate that the potent multivalent ligand that resulted can be used to probe the role of receptor assembly in TGF-β function.
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DOI：
10.1073/pnas.0602558103
发表时间：
2006-05-16
影响因子：
11.1
作者：
Allendorph, George P.;Vale, Wylie W.;Choe, Senyon
通讯作者：
Choe, Senyon
影响因子：
16
作者：
Chacko, BM;Qin, BY;Lin, K
通讯作者：
Lin, K
影响因子：
5.7
作者：
Boesen, CC;Radaev, S;Sun, PD
通讯作者：
Sun, PD
影响因子：
56.9
作者：
DeLano, WL;Ultsch, MH;Wells, JA
通讯作者：
Wells, JA
影响因子：
2.9
作者：
Deep, S;Walker, KP;Hinck, AP
通讯作者：
Hinck, AP