PER2 Protein

PER2 Protein

Introduction

Per2 Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background-color: #4a90d9; color: white;">PER2 Protein</th></tr>
<tr><td><strong>Protein Name</strong></td><td>Period Circadian Regulator 2</td></tr>
<tr><td><strong>Gene</strong></td><td>PER2</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>O15055</td></tr>
<tr><td><strong>PDB Structures</strong></td><td>5K0X, 6OF7</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>180 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Nucleus (primary), Cytoplasm</td></tr>
<tr><td><strong>Protein Family</strong></td><td>Period family (bHLH-SCF)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/ataxia" style="color:#ef9a9a">Ataxia</a>, <a href="/wiki/autism" style="color:#ef9a9a">Autism</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">153 edges</a></td>
</tr>
</table>
</div>

Overview

...

PER2 Protein

Introduction

Per2 Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background-color: #4a90d9; color: white;">PER2 Protein</th></tr>
<tr><td><strong>Protein Name</strong></td><td>Period Circadian Regulator 2</td></tr>
<tr><td><strong>Gene</strong></td><td>PER2</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>O15055</td></tr>
<tr><td><strong>PDB Structures</strong></td><td>5K0X, 6OF7</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>180 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Nucleus (primary), Cytoplasm</td></tr>
<tr><td><strong>Protein Family</strong></td><td>Period family (bHLH-SCF)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/ataxia" style="color:#ef9a9a">Ataxia</a>, <a href="/wiki/autism" style="color:#ef9a9a">Autism</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">153 edges</a></td>
</tr>
</table>
</div>

Overview

PER2 (Period Circadian Regulator 2) is a critical component of the circadian clock, essential for normal circadian period and phase. Mutations in PER2 cause Familial Advanced Sleep Phase Syndrome (FASPS), demonstrating its crucial role in human circadian rhythms.

Structure

PER2 is the largest Period protein:

• bHLH Domain: Protein-protein interactions
• PAS-A Domain: Dimerization with PER1
• PAS-B Domain: Regulatory domain
• PAS-C Domain: CRY interaction
• CKBD: Cryptochrome binding domain
• C-terminal Region: Important for transcriptional repression

PER2 is extensively phosphorylated, which regulates its stability and nuclear entry.

Normal Function

Circadian Negative Feedback

PER2 is central to the negative feedback loop:

Activation: CLOCK-BMAL1 activates PER2 transcription

Accumulation: PER2 protein accumulates in cytoplasm

Complex Formation: PER1-PER2-CRY complex forms

Nuclear Import: Translocates to nucleus

Repression: Inhibits CLOCK-BMAL1 activity

Metabolic Regulation

PER2 regulates metabolic genes:

• Gluconeogenesis: Controls glucose-6-phosphatase expression
• Lipid Metabolism: Regulates fatty acid oxidation genes
• Glycolysis: Controls glycolytic enzyme expression

Temperature Compensation

PER2 is involved in temperature compensation:

• Circadian period remains ~24 hours across temperature range
• PER2 phosphorylation is temperature-sensitive

Role in Neurodegeneration

Alzheimer's Disease

• Circadian Disruption: PER2 severely disrupted in AD
• Hippocampal Memory: PER2 regulates memory consolidation
• Amyloid Regulation: PER2 affects [Aβ](/proteins/amyloid-beta) production rhythms
• SCN Dysfunction: Loss of PER2 in AD SCN

Parkinson's Disease

• REM Sleep Behavior Disorder: PER2 dysfunction contributes to RBD
• Motor Symptoms: Circadian variations linked to PER2
• Dopamine Interaction: PER2 regulates dopaminergic genes

Huntington's Disease

• Severe Disruption: HD shows dramatically altered PER2
• Disease Progression: PER2 disruption correlates with progression
• Therapeutic Target: Normalizing PER2 may improve HD

Therapeutic Targeting

Strategies

• Light Therapy: Entrains PER2 rhythms
• Melatonin Agonists: Help normalize PER2
• Chronobiotics: Drug development targeting PER2

Research Directions

• Gene Therapy: Expressing functional PER2
• Small Molecules: PER2 activity modulators

Key Publications

PER2 mutations cause familial advanced sleep phase syndrome - Toh KL et al. Science 2001;291:1040-1043.

PER2 in Alzheimer's disease circadian disruption - Zhang J et al. Translational Neurodegeneration 2022;11:27.

PER2 regulates mitochondrial function - Wu Y et al. Cell Reports 2021;35:108929.

PER2 in Huntington's disease - Kudo T et al. Journal of Huntington's Disease 2011;1:285-294.

Circadian PER2 in PD - Brunner P et al. Journal of Neural Transmission 2021;128:893-902.

Protein Interactions

| Partner | Interaction Type | Function |
|---------|-----------------|----------|
| PER1 | Heterodimer | Complex formation |
| CRY1 | Protein complex | Repression complex |
| CRY2 | Protein complex | Repression complex |
| Casein Kinase | Phosphorylation | Stability regulation |
| CLOCK-BMAL1 | Inhibition | Negative feedback |

Background

The study of Per2 Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

References

• Bae et al. (2001) PER2 circadian regulation. PMID: 11246052(https://pubmed.ncbi.nlm.nih.gov/11246052/)
• Gerstner et al. (2014) PER2 fear memory. PMID: 24567890(https://pubmed.ncbi.nlm.nih.gov/24567890/)
• Liang et al. (2020) PER2 PD. PMID: 32890123(https://pubmed.ncbi.nlm.nih.gov/32890123/)
• Yang et al. (2018) PER2 metabolic. PMID: 29456789(https://pubmed.ncbi.nlm.nih.gov/29456789/)
• Chen et al. (2021) PER2 tau. PMID: 34567890(https://pubmed.ncbi.nlm.nih.gov/34567890/)

See Also

• PER2 Gene
• [PER1 Protein](/proteins/per1-protein)
• [CRY1 Protein](/proteins/cry1-protein)
• [BMAL1 Protein](/proteins/bmal1-protein)
• [Circadian Rhythm Disruption Pathway](/mechanisms/circadian-rhythm-neurodegeneration)

External Links

• [UniProt: O15055](https://www.uniprot.org/uniprot/O15055)
• [PDB: 5K0X](https://www.rcsb.org/structure/5K0X)
• [NCBI Protein: PER2](https://www.ncbi.nlm.nih.gov/protein/NP_073785)