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Related Concept Videos

Protein and Protein Structure02:15

Protein and Protein Structure

Proteins are one of the most abundant organic molecules in living systems and have the most diverse range of functions of all macromolecules. Proteins may be structural, regulatory, contractile, or protective. They may serve in transport, storage, or membranes; or they may be toxins or enzymes. Their structures, like their functions, vary greatly. They are all, however, amino acid polymers arranged in a linear sequence.
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Insulin: Biosynthesis, Chemistry, and Preparation01:25

Insulin: Biosynthesis, Chemistry, and Preparation

The endoplasmic reticulum (ER) of pancreatic β-cells synthesizes preproinsulin, which consists of a signal peptide, A and B chains, and a C-peptide. Preproinsulin is then cleaved and folded into proinsulin, which translocates to the Golgi apparatus for sorting and packaging into secretory granules. In these granules, enzymatic clipping generates insulin and C-peptide.
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Intrinsically Disordered Proteins02:18

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Intrinsically disordered proteins are a group of proteins that do not fold into specific three-dimensional structures. Their structural flexibility allows them to complement ordered proteins to perform functions that are inaccessible to rigid structures. They are more common in eukaryotes than prokaryotes and may either be exclusively intrinsically disordered or hybrid proteins, consisting of a mix of ordered and disordered regions. The absence of a rigid structure in these proteins can be...
Intrinsically Disordered Proteins02:18

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Conservation of Protein Domains Over Different Proteins02:26

Conservation of Protein Domains Over Different Proteins

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Computational Prediction of Amino Acid Preferences of Potentially Multispecific Peptide-Binding Domains Involved in Protein-Protein Interactions
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Solution structure of proinsulin: connecting domain flexibility and prohormone processing.

Yanwu Yang1, Qing-Xin Hua, Jin Liu

  • 1Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA. yanwu.yang@case.edu

The Journal of Biological Chemistry
|January 29, 2010
PubMed
Summary

Proinsulin folding is crucial for insulin production and preventing neonatal diabetes. This study used NMR to reveal proinsulin

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Molecular Endocrinology

Background:

  • Proinsulin folding ensures correct disulfide bonds for insulin function in pancreatic beta-cells.
  • Impaired proinsulin folding is linked to neonatal diabetes mellitus.
  • The precise structure of proinsulin remains challenging to determine due to its refractory nature to crystallization.

Purpose of the Study:

  • To characterize the structure of a monomeric proinsulin analogue using heteronuclear NMR spectroscopy.
  • To elucidate the role of proinsulin structure and flexibility in its processing and biosynthesis.
  • To provide a structural basis for understanding monogenic diabetes mellitus.

Main Methods:

  • Heteronuclear NMR spectroscopy was employed to study a monomeric proinsulin analogue.
  • Nuclear Overhauser effect (NOE) experiments were used to probe the order and flexibility of the connecting (C)-domain.
  • Chemical shift analysis of segmental (13)C(alpha/beta) was performed to assess secondary structure features.

Main Results:

  • Proinsulin contains a native-like insulin moiety (A- and B-domains) with a progressively less ordered C-domain.
  • While the BC junction is flexible, the CA junction and adjacent A-chain residues exhibit molten, alpha-helical-like features.
  • Flexibility at C-domain junctions is proposed to facilitate prohormone processing and cleavage site selection by proteases like SPC3 (PC1/3).

Conclusions:

  • The NMR-derived structure of proinsulin reveals key insights into its folding and flexibility.
  • Proinsulin's structural flexibility is essential for its efficient processing into mature insulin.
  • This structural understanding lays the groundwork for investigating insulin biosynthesis defects in diabetes mellitus.