Protein Denaturation and Folding:- Some Proteins Undergo Assisted Folding

Not all proteins fold spontaneously as they are synthesized in the cell. Folding for many proteins is facilitated by the action of specialized proteins. Molecular chaperones are proteins that interact with partially folded or improperly folded polypeptides, facilitating correct folding pathways or providing microenvironments in which folding can occur. Two classes of molecular chaperones have been well studied. Both are found in or ganisms ranging from bacteria to humans. The first class, a family of proteins called Hsp70, generally have a molecular weight near 70,000 and are more abundant in cells stressed by elevated temperatures (hence, heat shock proteins of Mr 70,000, or Hsp70). Hsp70 proteins bind to regions of unfolded polypeptides that are rich in hydrophobic residues, preventing inappropriate aggregation. These chaperones thus “protect” proteins that have been denatured by heat and peptides that are being synthesized (and are not yet folded). Hsp70 proteins also block the folding of certain proteins that must remain unfolded until they have been translocated across membranes (as described in Chapter 27). Some chaperones also facilitate the quaternary assembly of oligomeric proteins. The Hsp70 proteins bind to and release polypeptides in a cycle that also involves several other proteins (including a class called Hsp40) and ATP hydrolysis. Figure 4–30 illustrates chaperone assisted folding as elucidated for the chaperones DnaK and DnaJ in E. coli, homologs of the eukaryotic Hsp70 and Hsp40. DnaK and DnaJ were first identified as proteins required for in vitro replication of certain viral DNA molecules (hence the “Dna” designation).

FIGURE 4–30 Chaperones in protein folding. The cyclic pathway by which chaperones bind and release polypeptides is illustrated for the E. coli chaperone proteins DnaK and DnaJ, homologs of the eukaryotic chaperones Hsp70 and Hsp40. The chaperones do not actively promote the folding of the substrate protein, but instead prevent aggregation of unfolded peptides. For a population of polypeptides, some fraction of the polypeptides released at the end of the cycle are in the native conformation. The remainder are rebound by DnaK or are di verted to the chaperonin system (GroEL; see Fig. 4–31). In bacteria, a protein called GrpE interacts transiently with DnaK late in the cycle (step 3), promoting dissociation of ADP and possibly DnaJ. No eukaryotic analog of GrpE is known.

The second class of chaperones is called chaperonins. These are elaborate protein complexes required for the folding of a number of cellular proteins that do not fold spontaneously. In E. coli an estimated 10% to 15% of cellular proteins require the resident chaperonin system, called GroEL/GroES, for folding under normal conditions (up to 30% require this assistance when the cells are heat stressed). These proteins first became known when they were found to be necessary for the growth of certain bacterial viruses (hence the designation “Gro”). Unfolded proteins are bound within pockets in the GroEL complex, and the pockets are capped transiently by the GroES “lid” (Fig. 4–31). GroEL undergoes substantial conformational changes, coupled to ATP hydrolysis and the binding and release of GroES, which promote folding of the bound polypeptide. Al though the structure of the GroEL/GroES chaperonin is known, many details of its mechanism of action remain unresolved. Finally, the folding pathways of a number of proteins require two enzymes that catalyze isomerization reactions. Protein disulfide isomerase (PDI) is a widely distributed enzyme that catalyzes the inter change or shuffling of disulfide bonds until the bonds of the native conformation are formed. Among its functions, PDI catalyzes the elimination of folding intermediates with inappropriate disulfide cross-links. Peptide prolyl cis-trans isomerase (PPI)catalyzes the in terconversion of the cis and trans isomers of Pro pep tide bonds (Fig. 4–8b), which can be a slow step in the folding of proteins that contain some Pro residue pep tide bonds in the cis conformation. Protein folding is likely to be a more complex process in the densely packed cellular environment than in the test tube. More classes of proteins that facilitate protein folding may be discovered as the biochemical dissection of the folding process continues.

FIGURE 4–31 Chaperonins in protein folding. (a) A proposed pathway for the action of the E. coli chaperonins GroEL (a member of the Hsp60 protein family) and GroES. Each GroEL complex consists of two large pockets formed by two heptameric rings (each subunit Mr 57,000). GroES, also a heptamer (subunits Mr 10,000), blocks one of the GroEL pockets. (b) Surface and cut-away images of the GroEL/GroES complex (PDB ID 1AON). The cut-away (right) illustrates the large interior space within which other proteins are bound.

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مواضيع ذات صلة

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins: -Protein-Ligand Interactions Can Be Described Quantitatively

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins:- Myoglobin Has a Single Binding Site for Oxygen

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins:- Oxygen Can Be Bound to a Heme Prosthetic Group

Protein Denaturation and Folding:- Polypeptides Fold Rapidly by a Stepwise Process

Protein Denaturation and Folding: - Amino Acid Sequence Determines Tertiary Structure

Protein Tertiary and Quaternary Structures: -Protein Quaternary Structures Range from Simple Dimers to Large Complexes

Protein Tertiary and Quaternary Structures: -Protein Motifs Are the Basis for Protein Structural Classification

Protein Tertiary and Quaternary Structures: -Analysis of Many Globular Proteins Reveals Common Structural Patterns

Protein Tertiary and Quaternary Structures:- Globular Proteins Have a Variety of Tertiary Structures

Protein Tertiary and Quaternary Structures:- Myoglobin Provided Early Clues about the Complexity of Globular Protein Structure

Protein Tertiary and Quaternary Structures: -Structural Diversity Reflects Functional Diversity in Globular Proteins

Protein Tertiary and Quaternary Structures: -Fibrous Proteins Are Adapted for a Structural Function