Protein structure

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The protein structure is divided into different structural levels in biochemistry . The division into a hierarchy of primary structure ( amino acid sequence ), secondary structure , tertiary structure and quaternary structure was first proposed in 1952 by Kaj Ulrik Linderstrøm-Lang . With regard to the spatial arrangement of a protein, the term protein conformation is used synonymously. Changes in the spatial protein structure are called conformational changes . The protein structure is extremely important for the function of the protein. A faulty protein structure can lead to the failure of the original protein function.

The hierarchy of the structural levels

Folding and structure of the 1EFN protein

In biochemistry, a distinction is made between four hierarchically arranged structural levels in proteins :

Some proteins also arrange themselves in a “superstructure” or “superstructure” that goes beyond the quaternary structure. This is molecularly just as predetermined as the other structural levels. Examples of suprastructures are collagen in the collagen fibril, actin , myosin and titin in the sarcomere of the muscle fibril , and capsomeres in the capsid of enveloped viruses .

Formation of a spatial structure

The process of three-dimensional space filling of a protein takes place partly spontaneously during the translation , partly the cooperation of enzymes or chaperones is necessary. Also ligands affect protein structure so that some proteins depending on the complexation can take with cofactors or substrates different structures (see: conformational change ). This ability to change the spatial structure is necessary for many enzyme activities.

Disorders in the formation of a functional spatial structure are referred to as protein misfolding diseases . An example of this is Huntington's disease . Diseases that can be traced back to a malformation of the protein structure are called prion diseases . BSE or Alzheimer's disease are examples of such diseases. Also, diabetes mellitus type 2 is a proteopathy, it is based on an incorrect folding of the amylin . The spatial structure can also be destroyed by denaturation, due to heat, acids or bases and ionizing radiation .

Structure determination

Examples of protein structures from the PDB

Various experimental methods are available to elucidate the spatial protein structure:

  • In crystal structure analysis , a diffraction image of a protein crystal is created - usually using X-rays - from which its three-dimensional structure can then be calculated. The production of the single crystals required for this is very complicated and has not yet been possible for some proteins. Another problem with this method is that the structure of the proteins in the crystal does not necessarily correspond to the natural structure ( crystal packing ). A minimum size of the protein crystals is required for evaluable diffraction images. In order to obtain the required amount of substance, proteins that were produced by bacteria are often used. These sometimes do not have the post-translational modifications found in proteins of higher organisms .
  • The structure of a protein in solution can be determined using NMR spectroscopy , which corresponds more closely to the physiological (“natural”) conditions of the protein. Since atoms of the protein move in this state, there is no clear structure. In order to obtain a "clear" structure, the shown structures are usually averaged. Up to now, NMR spectroscopy cannot be carried out for all types of protein. The size in particular is a limiting factor here. Proteins> 30  kDa cannot yet be analyzed because the NMR results are so complex that no clear protein structure can be derived from them.
  • The structure depends on various physicochemical boundary conditions (such as pH , temperature , salt content , presence of other proteins). The Stokes radius of a native protein or a protein complex can be determined via native PAGE , size exclusion chromatography or by means of analytical ultracentrifugation . These methods can be combined with a cross-linking or an alanine scan .

A comprehensive collection of results from experiments on structure determination can be found in the Protein Data Bank .

Structure prediction

The prediction of spatial protein structures achieves good results when proteins with a similar sequence and known structure already exist. This enables so-called homology modeling , whereby the new sequence is mapped onto the sequence, the structure of which is known, and thus “fitted” into the structure. This technique is similar to sequence alignment .

The prediction is more difficult if no structures of similar amino acid sequences are known. The Levinthal paradox shows that the calculation of the energetically most favorable conformation is not feasible due to the many possibilities. In Bioinformatics great progress has been made in recent years, and various methods of de novo - or initio ab- developed -Strukturvorhersage. However, there is currently no reliable method for elucidating the structure of proteins.

The CASP competition ( critical assessment of techniques for protein structure prediction ) has been in place for several years to be able to compare new methods for structure prediction . In this competition, amino acid sequences of structures that crystallographers are currently working on are made available to the participants. Participants use their own methods to predict the structures. An evaluation team then compares the predictions with the experimentally determined structures.

The structure forecast was or is also the goal of several projects of distributed computing such as B. Rosetta @ home , POEM @ home , Predictor @ home and Folding @ home as well as the Human Proteome Folding Project . The game Foldit also makes use of the advantages of crowdsourcing to clarify the structure .

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  1. ↑ Linderstrøm-Lang, KU (1952): Proteins and Enzymes . In: Lane Medical Lectures . Vol. 6, pp. 1-115. Stanford University Publications, University Series, Medical Sciences, Stanford University Press.
  2. ↑ Christian B. Anfinsen received the Nobel Prize for Chemistry in 1972 "for his work on ribonuclease, in particular the connection between amino acid series and biologically active conformations" (official reason for the award of the Royal Swedish Academy of Sciences )
  3. ↑ Jeremy M. Berg , John L. Tymoczko , Lubert Stryer , Gregory J. Gatto, Jr.: Stryer Biochemistry . 7th edition. Springer Spectrum, 2013, ISBN 978-3-8274-2988-9 , pp. 25-59 .
  4. ↑ L. Skora: High-resolution characterization of structural changes involved in prion diseases and dialysis-related amyloidosis. (PDF; 4.6 MB) Dissertation, Georg-August-Universität Göttingen, 2009, p. Iii.

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