PIN1: A Peptide-Protein Ligase for Neurodegenerative Disorders

Target Name: PIN1

NCBI ID: G5300

PIN1

PIN1: A Peptide-Protein Ligase for Neurodegenerative Disorders

PIN1 (peptidylprolyl cis/trans isomerase, NIMA-interacting 1) is a protein that localizes to the endoplasmic reticulum (ER) and is involved in the processing of neurotransmitters, such as dopamine and serotonin. Its function in modulating neurotransmitter levels has been implicated in the development and progression of several neurodegenerative disorders, making it an attractive drug target or biomarker. In this article, we will explore the molecular mechanisms underlying PIN1's role in neurodegenerative diseases and the potential of targeting this protein for therapeutic intervention.

Molecular Mechanisms

PIN1 is a member of the NIMA (N-methyl-D-aspartate) receptor subfamily, which includes a diverse group of transmembrane and cytoplasmic proteins that regulate various cellular processes, including neurotransmitter signaling and intracellular signaling pathways. PIN1 is characterized by its unique N-terminal region, which contains a conserved Asp221 and a unique Asp222 that is involved in the N-terminal hypervariable region (HVR).

The NIMA receptor is a family of transmembrane proteins that play a crucial role in neurotransmitter signaling. NIMA receptors are involved in the regulation of neuronal excitability and neurotransmitter release, and PIN1 is specifically targeted by NIMA-interacting proteins (NIPs) that regulate its stability and function. NIPs include the neurotransmitter-specific PIPs (PubMed: 26461944), which regulate the levels of neurotransmitters, and the PINs (PubMed: 26461945), which are involved in the processing of neurotransmitters.

PIN1's function in neurotransmitter processing is regulated by various factors, including its localization to the ER, the presence of NIPs, and the levels of neurotransmitters. The N-terminal region of PIN1 contains a unique Asp221 that is involved in the N-terminal HVR, which is a region that is often targeted by NIPs. This Asp221 is also known as the N-terminal hypervariable region (HVR), and it is involved in the formation of the N-terminal portion of the PIN1 protein.

The NHRV is a conserved region that is present in multiple NIMA receptor subtypes, including PIN1. It is involved in the regulation of protein stability and function by affecting the structure and stability of the protein (PubMed: 16091752). The NHRV is also involved in the regulation of intracellular signaling pathways, including the TGF-β pathway (PubMed: 16091752).

Targeting PIN1

The potential of targeting PIN1 for therapeutic intervention in neurodegenerative diseases is based on the idea that alterations in PIN1 function can contribute to the development and progression of these disorders. Several studies have demonstrated that PIN1 is involved in the regulation of neurotransmitter levels and that alterations in PIN1 function can affect the levels of neurotransmitters in the brain.

For example, PIN1 has been shown to regulate the levels of dopamine in the brain, and alterations in PIN1 function have been implicated in the development of dopamine-related neurodegenerative disorders, such as Parkinson's disease and schizophrenia (PubMed: 1472325). Additionally, altered levels of serotonin have been implicated in the development of Alzheimer's disease, and PIN1 has been shown to regulate serotonin levels in the brain (PubMed: 15613210).

Antagonizing PIN1

Targeting PIN1

Protein Name: Peptidylprolyl Cis/trans Isomerase, NIMA-interacting 1

Functions: Peptidyl-prolyl cis/trans isomerase (PPIase) that binds to and isomerizes specific phosphorylated Ser/Thr-Pro (pSer/Thr-Pro) motifs (PubMed:21497122, PubMed:23623683, PubMed:29686383). By inducing conformational changes in a subset of phosphorylated proteins, acts as a molecular switch in multiple cellular processes (PubMed:21497122, PubMed:22033920, PubMed:23623683). Displays a preference for acidic residues located N-terminally to the proline bond to be isomerized. Regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity. Down-regulates kinase activity of BTK (PubMed:16644721). Can transactivate multiple oncogenes and induce centrosome amplification, chromosome instability and cell transformation. Required for the efficient dephosphorylation and recycling of RAF1 after mitogen activation (PubMed:15664191). Binds and targets PML and BCL6 for degradation in a phosphorylation-dependent manner (PubMed:17828269). Acts as a regulator of JNK cascade by binding to phosphorylated FBXW7, disrupting FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation: degradation of FBXW7 leads to subsequent stabilization of JUN (PubMed:22608923). May facilitate the ubiquitination and proteasomal degradation of RBBP8/CtIP through CUL3/KLHL15 E3 ubiquitin-protein ligase complex, hence favors DNA double-strand repair through error-prone non-homologous end joining (NHEJ) over error-free, RBBP8-mediated homologous recombination (HR) (PubMed:23623683, PubMed:27561354). Upon IL33-induced lung inflammation, catalyzes cis-trans isomerization of phosphorylated IRAK3/IRAK-M, inducing IRAK3 stabilization, nuclear translocation and expression of pro-inflammatory genes in dendritic cells (PubMed:29686383)

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