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Predicting protein function from structure: unique structural features of proteases.

ABSTRACT: We have noted consistent structural similarities among unrelated proteases. In comparison with other proteins of similar size, proteases have smaller than average surface areas, smaller radii of gyration, and higher C(alpha) densities. These findings imply that proteases are, as a group, more tightly packed than other proteins. There are also notable differences in secondary structure content between these two groups of proteins: proteases have fewer helices and more loops. We speculate that both high packing density and low alpha-helical content coevolved in proteases to avoid autolysis. By using the structural parameters that seem to show some separation between proteases and nonproteases, a neural network has been trained to predict protease function with over 86% accuracy. Moreover, it is possible to identify proteases whose folds were not represented during training. Similar structural analyses may be useful for identifying other classes of proteins and may be of great utility for categorizing the flood of structures soon to flow from structural genomics initiatives.

SUBMITTER: Stawiski EW

PROVIDER: S-EPMC18123 | biostudies-literature | 2000 Apr

REPOSITORIES: biostudies-literature

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Predicting protein function from structure: unique structural features of proteases.

Stawiski E W EW Baucom A E AE Lohr S C SC Gregoret L M LM

Proceedings of the National Academy of Sciences of the United States of America 20000401 8

We have noted consistent structural similarities among unrelated proteases. In comparison with other proteins of similar size, proteases have smaller than average surface areas, smaller radii of gyration, and higher C(alpha) densities. These findings imply that proteases are, as a group, more tightly packed than other proteins. There are also notable differences in secondary structure content between these two groups of proteins: proteases have fewer helices and more loops. We speculate that bot ...[more]

PMID: 10759560

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Project description:BackgroundThe chicken avidin gene family consists of avidin and several avidin related genes (AVRs). Of these gene products, avidin is the best characterized and is known for its extremely high affinity for D-biotin, a property that is utilized in numerous modern life science applications. Recently, the AVR genes have been expressed as recombinant proteins, which have shown different biotin-binding properties as compared to avidin.ResultsIn the present study, we have employed multiple biochemical methods to better understand the structure-function relationship of AVR proteins focusing on AVR2. Firstly, we have solved the high-resolution crystal structure of AVR2 in complex with a bound ligand, D-biotin. The AVR2 structure reveals an overall fold similar to the previously determined structures of avidin and AVR4. Major differences are seen, especially at the 1-3 subunit interface, which is stabilized mainly by polar interactions in the case of AVR2 but by hydrophobic interactions in the case of AVR4 and avidin, and in the vicinity of the biotin binding pocket. Secondly, mutagenesis, competitive dissociation analysis and differential scanning calorimetry were used to compare and study the biotin-binding properties as well as the thermal stability of AVRs and avidin. These analyses pinpointed the importance of residue 109 for biotin binding and stability of AVRs. The I109K mutation increased the biotin-binding affinity of AVR2, whereas the K109I mutation decreased the biotin-binding affinity of AVR4. Furthermore, the thermal stability of AVR2(I109K) increased in comparison to the wild-type protein and the K109I mutation led to a decrease in the thermal stability of AVR4.ConclusionAltogether, this study broadens our understanding of the structural features determining the ligand-binding affinities and stability as well as the molecular evolution within the protein family. This novel information can be applied to further develop and improve the tools already widely used in avidin-biotin technology.

Project description:Influenza A H15 viruses are members of a subgroup (H7-H10-H15) of group 2 hemagglutinin (HA) subtypes that include H7N9 and H10N8 viruses that were isolated from humans during 2013. The isolation of avian H15 viruses is, however, quite rare and, until recently, geographically restricted to wild shorebirds and waterfowl in Australia. The HAs of H15 viruses contain an insertion in the 150-loop (loop beginning at position 150) of the receptor-binding site common to this subgroup and a unique insertion in the 260-loop compared to any other subtype. Here, we show that the H15 HA has a high preference for avian receptor analogs by glycan array analyses. The H15 HA crystal structure reveals that it is structurally closest to H7N9 HA, but the head domain of the H15 trimer is wider than all other HAs due to a tilt and opening of the HA1 subunits of the head domain. The extended 150-loop of the H15 HA retains the conserved conformation as in H7 and H10 HAs. Furthermore, the elongated 260-loop increases the exposed HA surface and can contribute to antigenic variation in H15 HAs. Since avian-origin H15 HA viruses have been shown to cause enhanced disease in mammalian models, further characterization and immune surveillance of H15 viruses are warranted.IMPORTANCE In the last 2 decades, an apparent increase has been reported for cases of human infection by emerging avian influenza A virus subtypes, including H7N9 and H10N8 viruses isolated during 2013. H15 is the other member of the subgroup of influenza A virus group 2 hemagglutinins (HAs) that also include H7 and H10. H15 viruses have been restricted to Australia, but recent isolation of H15 viruses in western Siberia suggests that they could be spread more globally via the avian flyways that converge and emanate from this region. Here we report on characterization of the three-dimensional structure and receptor specificity of the H15 hemagglutinin, revealing distinct features and specificities that can aid in global surveillance of such viruses for potential spread and emerging threat to the human population.

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Predicting protein function from structure: unique structural features of proteases.

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Predicting protein function from structure: unique structural features of proteases.

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