Evolutionary plasticity of protein families: Coupling between sequence and structure variation

Panchenko, Anna R.; Wolf, Yuri I.; Panchenko, L. A.; Madej, Thomas

doi:10.1002/prot.20644

Cited by 46 publications

(51 citation statements)

References 44 publications

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“…The trend indicates that, in the case of the HADSF, the sequence diverges to a greater extent than does the structure. This deduction is consistent with the findings from earlier studies of single domain protein families (14)(15)(16).…”

Section: Resultssupporting

confidence: 93%

Consequences of domain insertion on sequence-structure divergence in a superfold

Pandya

Brown

Šali

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Although the universe of protein structures is vast, these innumerable structures can be categorized into a finite number of folds. New functions commonly evolve by elaboration of existing scaffolds, for example, via domain insertions. Thus, understanding structural diversity of a protein fold evolving via domain insertions is a fundamental challenge. The haloalkanoic dehalogenase superfamily serves as an excellent model system wherein a variable cap domain accessorizes the ubiquitous Rossmann-fold core domain. Here, we determine the impact of the cap-domain insertion on the sequence and structure divergence of the core domain. Through quantitative analysis on a unique dataset of 154 core-domain-only and capdomain-only structures, basic principles of their evolution have been uncovered. The relationship between sequence and structure divergence of the core domain is shown to be monotonic and independent of the corresponding type of domain insert, reflecting the robustness of the Rossmann fold to mutation. However, core domains with the same cap type share greater similarity at the sequence and structure levels, suggesting interplay between the cap and core domains. Notably, results reveal that the variance in structure maps to α-helices flanking the central β-sheet and not to the domain-domain interface. Collectively, these results hint at intramolecular coevolution where the fold diverges differentially in the context of an accessory domain, a feature that might also apply to other multidomain superfamilies. directed evolution | phosphoryl transferase | protein evolution | structural bioinformatics | HAD superfamily T he universe of protein structures is vast and diverse, yet these innumerable structures can be categorized into a finite number of folds (1). Ideally, the protein fold has a robust yet evolvable architecture to deliver chemistry, bind interaction partners, or provide scaffolding. A popular strategy for the acquisition of new function(s) is the topological alteration of the fold to provide a new evolutionary platform. More frequently, existing and stable scaffolds are elaborated to attain diversity that is due to accumulation of stochastic, independent, and near-neutral mutations in the protein sequence. In a large number of cases, the expansion of functional space has been achieved by the tandem fusion of two or three domains to form evolutionary modules known as supradomains (2). An analysis of catalytic domains fused to the nucleotide-binding Rossmann domain has revealed that the sequential order of their connections is conserved because each pairing arose from a single recombination event (3). Another common structural embellishment is that of domain insertion(s) into existing folds (4)-a strategy that is ubiquitous in all structural classes, i.e., all α, all β, α + β, and α/β (5). For example, members of the A, B, and Y DNA polymerase superfamilies, Rab geranylgeranyl transferase superfamily, and alcohol dehydrogenase superfamily have inserted different domains into the native fold to fine tun...

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Section: Resultssupporting

confidence: 93%

Consequences of domain insertion on sequence-structure divergence in a superfold

Pandya

Brown

Šali

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Recently, it was shown that AmVg is very enriched in replacement polymorphism (Kent et al, 2011). We notice that this polymorphism does not apply to the polyserine tract, which as a connector structure could be an ideal site for replacements (Panchenko et al, 2005). Sequence comparison across taxa suggests that the domain connector may be elongated in insects or possibly more broadly in Protostome animals, but serine residues are not present in all of these elongated connector sequences in insects, for example in the louse Pediculus humanus.…”

Section: Discussionmentioning

confidence: 77%

A vitellogenin polyserine cleavage site: highly disordered conformation protected from proteolysis by phosphorylation

Havukainen

Underhaug

Wolschin

et al. 2012

Journal of Experimental Biology

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SUMMARYVitellogenin (Vg) is an egg-yolk precursor protein in most oviparous species. In honeybee (Apis mellifera), the protein (AmVg) also affects social behavior and life-span plasticity. Despite its manifold functions, the AmVg molecule remains poorly understood. The subject of our structure-oriented AmVg study is its polyserine tract -a little-investigated repetitive protein segment mostly found in insects. We previously reported that AmVg is tissue specifically cleaved in the vicinity of this tract. Here, we show that, despite its potential for an open, disordered structure, AmVg is unexpectedly resistant to trypsin/chymotrypsin digestion at the tract. Our findings suggest that multiple phosphorylation plays a role in this resilience. Sequence variation is highly pronounced at the polyserine region in insect Vgs. We demonstrate that sequence differences in this region can lead to structural variation, as NMR and circular dichroism (CD) evidence assign different conformational propensities to polyserine peptides from the honeybee and the jewel wasp Nasonia vitripennis; the former is extended and disordered and the latter more compact and helical. CD analysis of the polyserine region of bumblebee Bombus ignitus and wasp Pimpla nipponica supports a random coil structure in these species. The spectroscopic results strengthen our model of the AmVg polyserine tract as a flexible domain linker shielded by phosphorylation. Supplementary material available online at

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“…Five outliers were located in coils (Table1). Loops have more evolutional plasticity than b-sheets or -helices (Panchenko et al, 2005), which makes these regions more difficult to model accurately by homology, as their sequence differs from the template structure. Our electrostatic map of the model shows a patch of positively charged residues on the b-sheets (Fig.5B).…”

Section: A Positively Charged Patch a Lipophilic Cavity And An Indicmentioning

confidence: 99%

Deconstructing honeybee vitellogenin: novel 40 kDa fragment assigned to its N terminus

Havukainen

Halskau

Skjærven

et al. 2011

Journal of Experimental Biology

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SUMMARYVitellogenin, an egg-yolk protein precursor common to oviparous animals, is found abundantly in honeybee workers -a caste of helpers that do not usually lay eggs. Instead, honeybee vitellogenin (180kDa) participates in processes other than reproduction: it influences hormone signaling, food-related behavior, immunity, stress resistance and longevity. The molecular basis of these functions is largely unknown. Here, we establish and compare the molecular properties of vitellogenin from honeybee hemolymph (blood) and abdominal fat body, two compartments that are linked to vitellogenin functions. Our results reveal a novel 40kDa vitellogenin fragment in abdominal fat body tissue, the main site for vitellogenin synthesis and storage. Using MALDI-TOF combined with MS/MS mass-spectroscopy, we assign the 40kDa fragment to the N terminus of vitellogenin, whereas a previously observed 150kDa fragment corresponded to the remainder of the protein. We show that both protein units are N glycosylated and phosphorylated. Focusing on the novel 40kDa fragment, we present a homology model based on the structure of lamprey lipovitellin that includes a conserved b-barrel-like shape, with a lipophilic cavity in the interior and two insect-specific loops that have not been described before. Our data indicate that the honeybee fat body vitellogenin experiences cleavage unlike hemolymph vitellogenin, a pattern that can suggest a tissue-specific role. Our experiments advance the molecular understanding of vitellogenin, of which the multiple physiological and behavioral effects in honeybees are well established. Supplementary material available online at

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Evolutionary plasticity of protein families: Coupling between sequence and structure variation

Cited by 46 publications

References 44 publications

Consequences of domain insertion on sequence-structure divergence in a superfold

Consequences of domain insertion on sequence-structure divergence in a superfold

A vitellogenin polyserine cleavage site: highly disordered conformation protected from proteolysis by phosphorylation

Deconstructing honeybee vitellogenin: novel 40 kDa fragment assigned to its N terminus

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