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Related Concept Videos

The Proteasome01:13

The Proteasome

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Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
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The Unfolded Protein Response01:37

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The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
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The Proteasome Structure01:17

The Proteasome Structure

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The ubiquitin-proteasome pathway is a well-known mechanism utilized by eukaryotic cells to remove cytoplasmic proteins that are misfolded, damaged, or no longer needed. In this pathway, the protein that needs to be eliminated undergoes a process called ubiquitination, where a chain of ubiquitin molecules is attached to the 48th lysine residue of the target protein. This ubiquitin modification helps the proteasome distinguish between a target protein and a healthy protein.
The proteasome is an...
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Covalently Linked Protein Regulators02:04

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Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
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Regulation of the Unfolded Protein Response01:31

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Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
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Protein Organization01:24

Protein Organization

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Proteins are polymers of amino acid residues. They are versatile and responsible for different cellular functions, including DNA replication, molecular transport, catalysis, and structural support. Proteins have a hierarchical structure comprising at least three levels of organization: primary, secondary, and tertiary structure. Some large proteins have a quaternary structure where individual protein subunits are linked together.
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AlphaFun: Structural-Alignment-Based Proteome Annotation Reveals why the Functionally Unknown Proteins (uPE1) Are So

Hengxin Pan1, Zhenqi Wu1, Wanting Liu1

  • 1MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.

Journal of Proteome Research
|April 16, 2024
PubMed
Summary

Researchers developed AlphaFun, a novel protein functional annotation strategy using deep-learning predicted structures. This method successfully annotated 99% of the human proteome, including previously unannotated proteins, advancing proteome understanding.

Keywords:
functional annotationsfunctional distributiongene ontology predictionuPE1

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Area of Science:

  • Proteomics
  • Structural Biology
  • Bioinformatics

Background:

  • Functional annotation of the human proteome remains a challenge, with many proteins lacking defined functions.
  • The Chromosome-centric Human Proteome Project (C-HPP) aims to identify and functionally annotate all human proteins.
  • A significant number of identified human proteins (uPE1 proteins) lack functional annotation due to limitations in sequence alignment and lack of structural data.

Purpose of the Study:

  • To develop and validate a new strategy for functional protein annotation.
  • To address the challenge of annotating uncharacterized human proteins (uPE1) and missing proteins.
  • To provide functional insights into evolutionarily young genes with tissue-specific expression.

Main Methods:

  • Utilized deep-learning predicted protein structures for structural alignment.
  • Developed a novel functional annotation strategy named AlphaFun.
  • Validated annotation accuracy using proteins with known functions.

Main Results:

  • Achieved functional annotation for 99% of the human proteome, including uPE1 and missing proteins.
  • Demonstrated that uPE1 proteins share functions with known proteins and exhibit limited tissue expression.
  • Identified uPE1 proteins as evolutionarily young genes with specialized functions.

Conclusions:

  • AlphaFun provides a scalable and accurate method for proteome-wide functional annotation.
  • The findings offer crucial insights for future research on uncharacterized and tissue-specific proteins.
  • The strategy is adaptable for functional annotation across different species.