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Folded, 3-D structure of ribonuclease A Anfinsen's dogma, also known as the thermodynamic hypothesis, is a postulate in
molecular biology Molecular biology is the branch of biology that seeks to understand the molecule, molecular basis of biological activity in and between Cell (biology), cells, including biomolecule, molecular synthesis, modification, mechanisms, and interactions ...
. It states that, at least for a small
globular protein 300px, 3-dimensional structure of hemoglobin, a globular protein. Globular proteins or spheroproteins are spherical ("globe-like") protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chains of amino ...
in its standard physiological environment, the
native structure
native structure
is determined only by the protein's
amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bonds. Due to carbon's ability to Catenation, c ...
sequence In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order theory, order matters. Like a Set (mathematics), set, it contains Element (mathematics), members (also called ''elements'', or ''terms''). ...

sequence
. The dogma was championed by the
Nobel Prize Laureate Nobel laureates of 2012 Alvin E. Roth, Brian Kobilka, Robert J. Lefkowitz">Brian_Kobilka.html" ;"title="Alvin E. Roth, Brian Kobilka">Alvin E. Roth, Brian Kobilka, Robert J. Lefkowitz, David J. Wineland, and Serge Haroche during the ceremony Th ...
Christian B. Anfinsen from his research on the folding of
ribonuclease A Pancreatic ribonucleases (, ''RNase'', ''RNase I'', ''RNase A'', ''pancreatic RNase'', ''ribonuclease I'', ''endoribonuclease I'', ''ribonucleic phosphatase'', ''alkaline ribonuclease'', ''ribonuclease'', ''gene S glycoproteins'', ''Ceratitis capi ...
. The postulate amounts to saying that, at the environmental conditions (temperature, solvent concentration and composition, etc.) at which folding occurs, the native structure is a unique, stable and kinetically accessible minimum of the free energy. In other words, there are three conditions for formation of a unique protein structure: *Uniqueness – Requires that the sequence does not have any other configuration with a comparable free energy. Hence the free energy minimum must be ''unchallenged''. *Stability – Small changes in the surrounding environment cannot give rise to changes in the minimum configuration. This can be pictured as a free energy surface that looks more like a funnel (with the native state in the bottom of it) rather than like a soup plate (with several closely related low-energy states); the free energy surface around the native state must be rather steep and high, in order to provide stability. *Kinetical accessibility – Means that the path in the free energy surface from the unfolded to the folded state must be reasonably smooth or, in other words, that the folding of the chain must not involve highly complex changes in the shape (like knots or other high order conformations).


Challenges to Anfinsen's dogma

Protein folding Protein folding is the physical process by which a protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of func ...

Protein folding
in cell is a highly complex process that involves transport of the newly synthesized proteins to appropriate cellular compartments through targeting, permanent misfolding, temporarily unfolded states,
post-translational modifications Post-translational modification (PTM) refers to the covalent A covalent bond is a chemical bond A chemical bond is a lasting attraction between atoms, ions or molecules that enables the formation of chemical compounds. The bond may resu ...
, quality control, and formation of
protein complexes is a protein complex functioning as a molecular biological machine. It uses protein dynamics#Global_flexibility:_multiple_domains , protein domain dynamics on Nanoscopic scale, nanoscales A protein complex or multiprotein complex is a group of tw ...
facilitated by chaperones. Some proteins need the assistance of
chaperone protein Chaperone proteins participate in the folding of over half of all mammalian proteins. In molecular biology, molecular chaperones are protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chains of amin ...
s to fold properly. It has been suggested that this disproves Anfinsen's dogma. However, the chaperones do not appear to affect the final state of the protein; they seem to work primarily by preventing
aggregation Aggregation may refer to: Business and economics * Aggregation problem (economics) * Purchasing aggregation, the joining of multiple purchasers in a group purchasing organization to increase their buying power * Community Choice Aggregation, the jo ...
of several protein molecules prior to the final folded state of the protein. However, at least some chaperones are required for the proper folding of their subject proteins. Many proteins can also undergo aggregation and misfolding. For example,
prion Prions are Protein folding, misfolded proteins with the ability to transmit their misfolded shape onto normal variants of the same protein. They characterize several fatal and transmissible neurodegenerative diseases in humans and many other anim ...

prion
s are stable conformations of proteins which differ from the native folding state. In
bovine spongiform encephalopathy Bovine spongiform encephalopathy (BSE), commonly known as mad cow disease, is a neurodegenerative disease of cattle. Symptoms include abnormal behavior, trouble walking, and weight loss. Later in the course of the disease the cow becomes unable ...
, native proteins re-fold into a different stable conformation, which causes fatal
amyloid Micrograph showing amyloid deposits (pink) in small bowel. Duodenum with amyloid deposition in lamina propria. Amyloid shows up as homogeneous pink material in lamina propria and around blood vessels. 20× magnification. Amyloids are aggregates ...
buildup. Other amyloid diseases, including
Alzheimer's disease Alzheimer's disease (AD), also referred to simply as Alzheimer's, is a neurodegenerative disease Neurodegeneration is the progressive loss of structure or function of neurons, including their death. Many neurodegenerative diseases—inc ...
and
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a chronic condition, long-term neurodegeneration, degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the diseas ...
, are also exceptions to Anfinsen's dogma. Some proteins have multiple native structures, and change their fold based on some external factors. For example, the KaiB protein complex switches fold throughout the day, acting as a clock for cyanobacteria. It has been estimated that around 0.5–4% of PDB proteins switch folds. The switching between alternative structures is driven by interactions of the protein with small ligands or other proteins, by chemical modifications (such as
phosphorylation In chemistry Chemistry is the science, scientific study of the properties and behavior of matter. It is a natural science that covers the Chemical element, elements that make up matter to the chemical compound, compounds composed of atoms, ...
) or by changed environmental conditions, such as temperature, pH or
membrane potential Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential The electric potential (also called the ''electric field potential'', potential drop, the electrostatic potential) is the amount of wo ...

membrane potential
. Each alternative structure may either correspond to the global minimum of free energy of the protein at the given conditions or be kinetically trapped in a higher
local minimum In mathematical analysis, the maxima and minima (the respective plurals of maximum and minimum) of a function, known collectively as extrema (the plural of extremum), are the largest and smallest value of the function, either within a given ra ...
of free energy.


References


Further reading

* * * {{cite journal , vauthors=Moore S, Stein WH , title=Chemical structures of pancreatic ribonuclease and deoxyribonuclease , journal=Science , volume=180 , issue=4085 , year=1973 , pages=458–464 , pmid=4573392 , doi=10.1126/science.180.4085.458, bibcode=1973Sci...180..458M
Profiles in Science: The Christian B. Anfinsen Papers-Articles
Molecular biology Protein structure
HypothesesA hypothesis (plural hypotheses) is a proposed explanation for a phenomenon. For a hypothesis to be a scientific hypothesis, the scientific method requires that one can test it. In contrast, Conjectures are statements which cannot necessarily be emp ...