Structural Basis for High-Affinity Peptide Inhibition of Human Pin1

Zhang, Yan; Daum, Sebastian; Wildemann, Dirk; Zhou, Xiao Zhen; Verdecia, Mark A.; Bowman, M.E.; Lücke, Christian; Hunter, Tony; Lu, Kun-Ping; Fischer, Gunter; Noel, Joseph P.

doi:10.1021/cb7000044

Cited by 125 publications

(199 citation statements)

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“…Different research groups are currently developing Pin1 small-molecule inhibitors, whose efficacy in anticancer therapy should be tested in vivo. [32][33][34] Furthermore, we have found that the other two members of the pocket protein family, namely p130/pRb2 and p107, are substrates of Pin1. As in T98G cells the Pin1 and pRb interaction plays a major role in the G1/S cell cycle control, it would be interesting to analyze Pin1, pRb2/p130, and p107 in other cancer cells or other physiological processes.…”

Section: Discussionmentioning

confidence: 92%

Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1

et al. 2012

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Inactivation of the retinoblastoma protein (pRb) by phosphorylation triggers uncontrolled cell proliferation. Accordingly, activation of cyclin-dependent kinase (CDK)/cyclin complexes or downregulation of CDK inhibitors appears as a common event in human cancer. Here we show that Pin1 (protein interacting with NIMA (never in mitosis A)-1), a peptidylprolyl isomerase involved in the control of protein phosphorylation, is an essential mediator for inactivation of the pRb. Our results indicate that Pin1 controls cell proliferation by altering pRb phosphorylation without affecting CDK and protein phosphatase 1 and 2 activity. We demonstrated that Pin1 regulates tumor cell proliferation through direct interaction with the spacer domain of the pRb protein, and allows the interaction between CDK/cyclin complexes and pRb in mid/late G1. Phosphorylation of pRb Ser 608/612 is the crucial motif for Pin1 binding. We propose that Pin1 selectively boosts the switch from hypo-to hyper-phosphorylation of pRb in tumor cells. In addition, we demonstrate that the CDK pathway is responsible for the interaction of Pin1 and pRb. Prospectively, our findings therefore suggest that the synergism among CDK and Pin1 inhibitors holds great promise for targeted pharmacological treatment of cancer patients, with the possibility of reaching high effectiveness at tolerated doses. The retinoblastoma protein (pRb), the product of the RB1 gene (i.e., the tumor-suppressor gene involved in hereditary and sporadic retinoblastoma pathogenesis), is mainly responsible for the control of cell proliferation via two different mechanisms. The first is based on the interaction between pRb and different chromatin-modifying enzymes: pRb interacts with histone deacetylases (HDACs) 1, 2, and 3, histone methylase SUV39H1, and chromatin-remodeling enzymes Brg1 and Brm, thus repressing gene expression. 1 The second mechanism involves pRb controlling the cell cycle through interaction with the E2F family of transcription factors 2 in a phosphorylation-dependent way: in early and mid G1, the protein complex D-type cyclins/CDK4, 6 whereas in late G1, cyclins E(A)/CDK2 gradually phosphorylate pRb. Hyperphosphorylated pRb releases E2F transcription factors and allows the expression of genes that mediate entry into the S phase. 3 As pRb protein holds a central role in the cell cycle, its inactivation is necessary for enabling cancer cell proliferation. Different mechanisms of pRb inactivation have been described, although inactivation through phosphorylation is most common in human sporadic cancers. In this context, cyclin D1 overexpression induces CDK4/6 activation and thus pRb hyperphosphorylation. 4,5 In addition, the cyclindependent kinase (CDK) inhibitory partner, p16 protein (i.e.,

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Section: Discussionmentioning

confidence: 92%

Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1

et al. 2012

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“…More specific Pin1 inhibitors with less side effects are required. Promising candidates are the substituted aryl 1-indanyl ketones (53) and a series of specific D-phospho-Thr-containing peptides (54,55). Such inhibitors might not only be useful in studying the functional relevance of Pin1 in vivo; they could also provide the therapeutic basis to treat pathological conditions in which Pin1 is aberrantly upregulated, such as cancer (8).…”

Section: Discussionmentioning

confidence: 99%

Juglone Inactivates Cysteine-rich Proteins Required for Progression through Mitosis

Fila

Metz

Sluijs

2008

Journal of Biological Chemistry

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The parvulin peptidyl-prolyl isomerase Pin1 catalyzes cistrans isomerization of p(S/T)-P bonds and might alter conformation and function of client proteins. Since the trans conformation of p(S/T)-P bonds is preferred by protein phosphatase 2A (PP2A), Pin1 may facilitate PP2A-mediated dephosphorylation. Juglone irreversibly inhibits parvulins and is often used to study the function of Pin1 in vivo. The drug prevents dephosphorylation of mitotic phosphoproteins, perhaps because they bind Pin1 and are dephosphorylated by PP2A. We show here however that juglone inhibited post-mitotic dephosphorylation and the exit of mitosis, independent of Pin1. This effect involved covalent modification of sulfhydryl groups in proteins essential for metaphase/anaphase transition. Particularly cytoplasmic proteins with a high cysteine content were vulnerable to the drug. Alkylation of sulfhydryl groups altered the conformation of such proteins, as evidenced by the disappearance of antibody epitopes on tubulin and the mitotic checkpoint component BubR1. The latter activates the anaphase-promoting complex/ cyclosome, which degrades regulatory proteins, such as cyclin B1 and securins, and is required for mitotic exit. Indeed, juglone-treated cells failed to assemble a mitotic spindle, which correlated with perturbed microtubule dynamics, loss of immunodetectable tubulin, and formation of tubulin aggregates. Juglone also prevented degradation of cyclin B1, independently of the Mps1-controlled mitotic spindle checkpoint. Since juglone affected cell cycle progression at several levels, more specific drugs need to be developed for studies of Pin1 function in vivo. Peptidyl-prolyl isomerases (PPIases)2 accelerate the cis-trans conversion of peptide bonds preceding prolyl residues, which can cause alterations in protein conformation (e.g. see Refs. 1 and 2). PPIases have been grouped into cyclophilin, FK506-binding protein, and parvulin subfamilies (see Ref. 3), for which distinct pharmacological inhibitors are available. The parvulin group is irreversibly inhibited by juglone (4). Pin1 comprises an N-terminal type IV WW domain, which determines phosphorylation-specific protein-protein interactions, and a C-terminal PPIase domain that harbors the catalytic center (see Ref. 5). Pin1 is a unique PPIase, because it preferably binds to side chain-phosphorylated S/T-P moieties in numerous proteins, including crucial cell cycle regulators or proteins that become phosphorylated immediately prior to cell division (6, 7). Isomerization of the p(S/T)-P peptide bond regulates, for instance, localization and phosphorylation status of Pin1 client proteins (see Ref. 5). Pin1 is therefore a regulator that, in concert with proline-directed kinases, phosphatases, and ubiquitin ligases, controls the cell cycle (see Refs. 5 and 8). Pin1 is possibly a cancer target gene, because its overexpression enhances transformed phenotypes induced by oncogenic Ras and Neu (see (5)). Pin1 is overexpressed in many human cancers, and its overexpression correlates with poor...

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“…These inhibitors contained non-proteogenic amino acids and blocked cell cycle progression in HeLa cells in a dose-dependent manner. In addition, high resolution crystal structures of the D-and L-forms of two of these pentameric inhibitors have been published (Zhang et al, 2007). In the structure of the L-peptide complex the pThr-Pip (piperidine-2-carboxylic acid) carbonyl group faces away from the side chains of Arg 68 , Gln 131 and Ser 154 , resulting in an ω bond angle close to the cis conformation, whereas in the D-peptide-complex the carbonyl moiety forms a hydrogen bond with the Ser 154 hydroxyl group.…”

Section: Peptidic Inhibitors and Substrate Analogsmentioning

confidence: 99%

Structure and function of the human parvulins Pin1 and Par14/17

Matena

Rehic

Hönig

et al. 2018

Biological Chemistry

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Parvulins belong to the family of peptidyl-prolyl cis/trans isomerases (PPIases) assisting in protein folding and in regulating the function of a broad variety of proteins in all branches of life. The human representatives Pin1 and Par14/17 are directly involved in processes influencing cellular maintenance and cell fate decisions such as cell-cycle progression, metabolic pathways and ribosome biogenesis. This review on human parvulins summarizes the current knowledge of these enzymes and intends to oppose the well-studied Pin1 to its less wellexamined homolog human Par14/17 with respect to structure, catalytic and cellular function.

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Structural Basis for High-Affinity Peptide Inhibition of Human Pin1

Cited by 125 publications

References 58 publications

Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1

Retinoblastoma tumor-suppressor protein phosphorylation and inactivation depend on direct interaction with Pin1

Juglone Inactivates Cysteine-rich Proteins Required for Progression through Mitosis

Structure and function of the human parvulins Pin1 and Par14/17

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