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On the effects of structure and function on protein evolution
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Many proteins can be described as working machines that make sure that everything functions in the cell. Their specific molecular functions are largely dependent on their three-dimensional structures, which in turn are mainly predetermined by their linear sequences of amino acid residues. Therefore, there is a relation between the sequence, structure and function of a protein, in which knowledge about the structure is crucial for understanding the functions. The structure is generally difficult to determine experimentally, but should in principle be possible to predict from the sequence by computational methods. The instructions of how to build the linear proteins sequences are copied during cell division and are passed on to successive generations. Although the copying process is a very efficient and accurate system, it does not function correctly on every occasion. Sometimes errors, or mutations can result from the process. These mutations gradually accumulate over time, so that the sequences and thereby also the structures and functions of proteins evolve overtime. This thesis is based on four papers concerning the relationship between function, structure and sequence and how it changes during the evolution of proteins. Paper I shows that the structural change is linearly related to sequence change and that structures are 3 to 10 times more conserved than sequences. In Paper II and Paper III we investigated non-helical structures and polar residues, respectively, positioned in the nonpolar membrane core environment of α-helical membrane proteins. Both types were found to be evolutionary conserved and functionally important. Paper IV includes the development of a method to predict the residues in α-helical membrane proteins that after folding become exposed to the solvent environment.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University , 2010. , 48 p.
Keyword [en]
protein, structure, function, evolution, membrane
National Category
Biochemistry and Molecular Biology
Research subject
URN: urn:nbn:se:su:diva-35872ISBN: 978-91-7155-980-7OAI: diva2:288611
Public defence
2010-02-19, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.Available from: 2010-01-28 Created: 2010-01-20 Last updated: 2014-11-10Bibliographically approved
List of papers
1. Structure is three to ten times more conserved than sequence--a study of structural response in protein cores
Open this publication in new window or tab >>Structure is three to ten times more conserved than sequence--a study of structural response in protein cores
2009 (English)In: Proteins, ISSN 0887-3585, Vol. 77, no 3, 499-508 p.Article in journal (Refereed) Published
Abstract [en]

Protein structures change during evolution in response to mutations. Here, we analyze the mapping between sequence and structure in a set of structurally aligned protein domains. To avoid artifacts, we restricted our attention only to the core components of these structures. We found that on average, using different measures of structural change, protein cores evolve linearly with evolutionary distance (amino acid substitutions per site). This is true irrespective of which measure of structural change we used, whether RMSD or discrete structural descriptors for secondary structure, accessibility, or contacts. This linear response allows us to quantify the claim that structure is more conserved than sequence. Using structural alphabets of similar cardinality to the sequence alphabet, structural cores evolve three to ten times slower than sequences. Although we observed an average linear response, we found a wide variance. Different domain families varied fivefold in structural response to evolution. An attempt to categorically analyze this variance among subgroups by structural and functional category revealed only one statistically significant trend. This trend can be explained by the fact that beta-sheets change faster than alpha-helices, most likely due to that they are shorter and that change occurs at the ends of the secondary structure elements.

urn:nbn:se:su:diva-34574 (URN)10.1002/prot.22458 (DOI)000270849900002 ()19507241 (PubMedID)
Available from: 2010-01-11 Created: 2010-01-11 Last updated: 2014-11-10Bibliographically approved
2. Coils in the membrane core are conserved and functionally important
Open this publication in new window or tab >>Coils in the membrane core are conserved and functionally important
2008 (English)In: Journal of Molecular Biology, ISSN 0022-2836, Vol. 380, no 1, 170-180 p.Article in journal (Refereed) Published
Abstract [en]

With the increasing number of available α-helical transmembrane (TM) protein structures, the traditional picture of membrane proteins has been challenged. For example, reentrant regions, which enter and exit the membrane at the same side, and interface helices, which lie parallel with the membrane in the membrane–water interface, are common. Furthermore, TM helices are frequently kinked, and their length and tilt angle vary. Here, we systematically analyze 7% of all residues within the deep membrane core that are in coil state. These coils can be found in TM-helix kinks as major breaks in TM helices and as parts of reentrant regions.

Coil residues are significantly more conserved than other residues. Due to the polar character of the coil backbone, they are either buried or located near aqueous channels. Coil residues are frequently found within channels and transporters, where they introduce the flexibility and polarity required for transport across the membrane. Therefore, we believe that coil residues in the membrane core, while constituting a structural anomaly, are essential for the function of proteins.

Amino Acid Sequence, Amino Acid Substitution, Conserved Sequence, Hydrogen Bonding, Ion Channels/chemistry, Membrane Proteins/*chemistry/*metabolism, Membrane Transport Proteins/chemistry, Models; Molecular, Protein Structure; Secondary, Software, Structure-Activity Relationship
urn:nbn:se:su:diva-14856 (URN)10.1016/j.jmb.2008.04.052 (DOI)000257469600014 ()18511074 (PubMedID)
Available from: 2008-11-20 Created: 2008-11-20 Last updated: 2014-11-10Bibliographically approved
3. Polar residues in the membrane core are conserved and directly involved in function
Open this publication in new window or tab >>Polar residues in the membrane core are conserved and directly involved in function
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Here, we have analyzed strongly polar residues within the membrane core of alpha-helicalmembrane proteins. Although underrepresented, they constitute as much as 9% of all coreresidues and they are found to be more conserved than other core residues. The reason for theconservation is twofold. First, the residues are mainly buried within the proteins and secon-darily they are found to often be directly involved in the function of the protein. Even if mostpolar sidechains are buried, the actual polar groups often border water filled cavities. In addi-tion, polar residues are often directly involved in binding of small compounds in channels andtransporters or long-term interactions with prosthetic groups. The interactions with prostheticgroups in photosynthetic proteins and oxidoreductase proteins are dominated by histidines andflexibility is provided mainly by prolines. It was also predicted that in human membrane pro-teins the polar core residues are overrepresented among active transporter proteins as well asamong GPCRs, while underrepresented in families with few transmembrane regions, such asnon-GPCR receptors. In GPCRs asparagin, histidine and proline residues are overrepresentedwhile in the active transporters prolines and glutamates are most frequent.

Membrane proteins, polar residues, conservation, accessibility, functional residues
urn:nbn:se:su:diva-35894 (URN)
Available from: 2010-01-21 Created: 2010-01-20 Last updated: 2014-11-10Bibliographically approved
4. MPRAP: An accessibility predictor for α-helical transmembrane proteins
Open this publication in new window or tab >>MPRAP: An accessibility predictor for α-helical transmembrane proteins
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background:    During the folding of a protein some residues will become exposed to the environmentwhile others will become buried in the protein interior. For water soluble proteins it is en-ergetically favorable to bury hydrophobic residues and expose polar and charged residues tothe surrounding water. However, transmembrane proteins face three distinct environments; ahydrophobic lipid environment inside the membrane, a hydrophilic water environment outsidethe membrane and a interface region rich in phospholipid head-groups. Therefore, for ener-getic reasons the accessible surfaces of transmembrane proteins need to expose different typesof residues at different locations.    Results:    In a set of structurally determined transmembrane proteins it was found that solvent ex-posed residues are quite different inside compared to outside the membrane. In contrast,residues buried within the interior of the protein are much more similar. Further, we foundthat state-of-the-art predictors for surface area are optimized for one of the environments andtherefore perform badly in the other environment. To circumvent this problem we developeda new predictor, MPRAP, that performs well both inside and outside the membrane regions aswell as being better than a combination of specialized predictors. A web-server of MPRAP isavailable at    Conclusion:    By including complete α-helical transmembrane proteins in the training we developed apredictor that accurately predicts accessibility both inside and outside the membrane. This pre-dictor can aid in predicting 3D-structure, predicting functional relevance of individual residuesand identification of erroneous protein structures.

urn:nbn:se:su:diva-35890 (URN)
Available from: 2010-01-21 Created: 2010-01-20 Last updated: 2014-11-10Bibliographically approved

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