Proteins are conformationally dynamic molecules that can fold into their functionally competent conformation in as little as a few milliseconds. Moreover, they often can refold if their con formation becomes disrupted, a process called renaturation. How are the remarkable speed and fidelity of protein folding attained? In nature, folding into the native state occurs too rapidly to be the product of a random, haphazard search of all possible structures. Denatured proteins are not just random coils. Native contacts are favored, and regions of the native structure persist even in the denatured state. Following are factors that facilitate and are basic mechanistic features of protein folding–refolding.

Native Conformation of a Protein Is Thermodynamically Favored

 Since the biologically relevant—or native—conformation of a protein generally is the one that is most energetically favored, knowledge of the native conformation is specified in the primary sequence. However, the number of distinct combinations of phi and psi angles that can potentially be adopted by even a relatively small—100 amino acid long—polypeptide is unbelievably vast: 3198. Hence, it would require billions of years for a polypeptide to arrive at its native conformation if folding occurred via the random exploration of all possible conformations. Clearly, in nature, protein folding takes place in a more orderly and guided fashion.

Folding Is Modular

Protein folding generally occurs via a stepwise process. In the first stage, as the newly synthesized polypeptide emerges from the ribosome, short segments fold into secondary structural units. Initiating folding contranslationally, that is, as a protein is synthesized, simplifies the folding process by allowing newly formed segments of organized structure to serve as scaffolds to direct folding of subsequent segments toward the native conformation and away from unproductive alternatives. In the second stage, the hydrophobic regions of this initial set secondary and supersecondary elements segregate together away from water to form the hydrophobic core of a “molten globule.” Within the molten globule, these secondary structure modules rearrange or even morph into other types of secondary structural forms until the mature conformation of the protein is attained. This process is orderly, but not rigid. For oligomeric proteins, individual protomers tend to fold before they associate with other subunits.

Auxiliary Proteins Assist Folding

Under appropriate laboratory conditions, many proteins will spontaneously refold after being denatured (ie, unfolded) by mild heating or treatment with acid or base, chaotropic agents, or detergents. However, most proteins fail to spontaneously refold in vitro and, for those that do, the process is very slow— minutes to hours. In most cases, denatured proteins congeal together to form insoluble aggregates, disordered complexes of unfolded or partially folded polypeptides held together predominantly by hydrophobic interactions. While the native conformation may be thermodynamically favored, aggregates nonetheless generally occupy deep local energy wells that are extremely difficult to escape from. Thus, they represent unproductive and oftentimes cytotoxic dead ends in the folding process. Cells employ auxiliary proteins to speed the process of folding and to guide its trajectory away from aggregate formation and toward a productive conclusion.

Chaperones

Chaperone proteins participate in the folding of over half of all mammalian proteins. The hsp70 (70-kDa heat shock protein) family of chaperones binds short sequences of hydrophobic amino acids that emerge while a new polypeptide is being synthesized, shielding them from solvent as polypeptide synthesis continues. By preventing aggregation, chaperones provide an opportunity for appropriate secondary structural elements to form prior to their coalescence into a molten globule. The hsp60 family of chaperones, sometimes called chaperonins, differs in sequence and structure from hsp70 and its homologs. Hsp60 acts later in the folding process, often together with an hsp70 chaperone. The central cavity of the donut-shaped hsp60 oligomer provides a sheltered nonpolar environment in which a misfolded polypeptide can unfold and subsequently refold into its physiologically functional conformation.

Protein Disulfide Isomerase

 Disulfide bonds between and within polypeptides stabilize tertiary and quaternary structures. The process is initiated by the enzyme protein sulfhydryl oxidase, which catalyzes the oxidation of cysteine residues to form disulfide bonds. However, disulfide bond formation is nonspecific—a given cysteine can form a disulfide bond with any accessible cysteinyl residue. By catalyzing disulfide exchange, the rupture of an S—S bond and its reformation with a different partner cysteine, protein disulfide isomerase facilitates the formation of disulfide bonds that stabilize a protein’s native conformation. Since many eukaryotic sulfhydryl oxidases are flavin-dependent, dietary riboflavin deficiency often is accompanied by an increased incidence of improper folding of disulfide-containing proteins.

Proline-cis, trans-Isomerization

All X-Pro peptide bonds—where X represents any residue— are synthesized in the trans configuration. However, of the X-Pro bonds of mature proteins, approximately 6% are cis.

The cis configuration is particularly common in β turns. Isomerization from trans to cis is catalyzed by enzymes called proline-cis, trans-isomerases, also known as cyclophilins (Figure 1). In addition to promoting the maturation of native proteins, cyclophilins also participate in the folding of proteins expressed as a consequence of viral infection. Consequently, cyclophilins are being pursued as targets for the development of drugs, such as cyclosporine and Alisporivir, for the treatment of HIV, hepatitis C, and other virally trans mitted diseases.

Fig1. Isomerization of the N-α1 prolyl peptide bond from a cis to a trans configuration relative to the backbone of the polypeptide.

اخر الاخبار

اخبار العتبة العباسية المقدسة

طوال الشهر الفضيل.. قسم الشؤون الخدمية يقدم أكثر من 42 ألف صندوق ماء للزائرين

بمشاركة 142 منتسبًا.. قسم الشؤون الدينية يختتم دورته الفقهية التطويرية السادسة

قسم بين الحرمين: قدمنا أكثر من 50 ألف وجبة إفطار للزائرين خلال شهر رمضان المبارك

المجمع العلمي يختتم نشاطاته القرآنية الرمضانية في المثنى

المزيد

الآخبار الصحية

كوب قبل النوم.. مشروب طبيعي يحارب الأرق

دون أدوية.. طريقة طبيعية لخفض ضغط الدم بفعالية مذهلة

المعكرونة ليست عدوك.. كيف تصبح جزءا من وجبة صحية متوازنة؟

دراسة: تناول القهوة يوميا يخفض خطر الإصابة بالاضطرابات النفسية

المزيد

الآخبار التكنلوجية

علماء روس يخططون لبناء منشأة للكشف عن المادة المظلمة

ثاني أكسيد الكربون ليس تهديدا للمناخ فقط.. بل لصحة الإنسان أيضا!

ديدان الأرض تكشف تلوث التربة بالمعادن الثقيلة

خبير أرصاد جوية: ظاهرة النينيو القادمة قد تكون الأقوى خلال 10 سنوات

المزيد

مواضيع ذات صلة

X-Ray Crystallography

Tertiary & Quaternary Structure of proteins

Proteomics & the Proteome

Mass Spectrometers Come in Various Configurations

Edman Devised the First Practical Method for Peptide Sequencing

Parathyroid Hormone-Related Protein

Parathyroid Hormone

Vitamin D and 1α,25(OH)2D3

Calcium and Phosphorus Homeostasis

Leukotrienes in Human Disease

Prostaglandins and Cancer

Sanger Was the First to Determine the Sequence of a Polypeptide