Functional implications of interleukin‐1β based on the three‐dimensional structure

Veerapandian, B.; Gilliland, Gary L.; Raag, Reetta; Svensson, Anders L.; Masui, Yoshihiro; Hirai, Yoshikatsu; Poulos, T.L.

doi:10.1002/prot.340120103

Cited by 79 publications

(56 citation statements)

References 48 publications

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“…IL-1β contains three trefoil subunits (βββ-loop-β), in which six β-strands (strands 1,4,5,8,9,12) form the barrel and six β-strands (strands 2, 3, 6, 7, 10, 11) form a hairpin cap (12)(13)(14). The protein populates a well-defined structured intermediate on the folding pathway in which the central strands (β-strands 6-10) form early followed by packing of the N-and C-terminal strands to close the β-barrel (15,16).…”

Section: Resultsmentioning

confidence: 99%

β-Bulge triggers route-switching on the functional landscape of interleukin-1β

Capraro

Roy

Onuchic

et al. 2012

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

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Proteins fold into three-dimensional structures in a funneled energy landscape. This landscape is also used for functional activity. Frustration in this landscape can arise from the competing evolutionary pressures of biological function and reliable folding. Thus, the ensemble of partially folded states can populate multiple routes on this journey to the native state. Although protein folding kinetics experiments have shown the presence of such routes for several proteins, there has been sparse information about the structural diversity of these routes. In addition, why a given protein populates a particular route more often than another protein of similar structure and sequence is not clear. Whereas multiple routes are observed in theoretical studies on the folding of interleukin-1β (IL-1β), experimental results indicate one dominant route where the central portion of the protein folds first, and is then followed by closure of the barrel in this β-trefoil fold. Here we show, using a combination of computation and experiment, that the presence of functionally important regions like the β-bulge in the signaling protein IL-1β strongly influences the choice of folding routes. By deleting the β-bulge, we directly observe the presence of routeswitching. This route-switching provides a direct link between route selection and the folding and functional landscapes of a protein.pulse-labeling | geometric frustration T he energy landscape theory and the funnel concept provide a solution to the protein folding search problem (1). The presence of multiple routes to the native state within this funnel is evident in both simulation and experimental studies (2) and is thought to add to the robustness of the landscape. The question remains, what factors control the route selection for folding? There is speculation that functional residues are a hindrance to folding and may add heterogeneity and roughness to the landscape (2-8). These residues need to be conserved for the protein to function correctly and therefore cannot be optimized for folding. However, the rest of the protein can evolve to make folding more efficient by making the energy landscape more funneled. Thus, it is possible that the most frustrated parts of the protein are the functional sites within the native structure. We hypothesize that functional regions within a protein that are geometrically frustrated drive route selection.The 12 β-stranded inflammatory cytokine, interleukin-1β (IL-1β), is an excellent system to probe the modulation of the folding landscape by perturbing functional regions. Structure-based models (where native interactions dominate the energy function) have identified the functionally important β-bulge (located between β-strands 4 and 5) as a region that is geometrically frustrated and suggest that contacts with this region direct folding route selection (9, 10). Deletion of the β-bulge maintains high affinity receptor binding but abrogates signaling activity, effectively converting the agonist into an antagonist molecule (11). To experime...

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Section: Resultsmentioning

confidence: 99%

β-Bulge triggers route-switching on the functional landscape of interleukin-1β

Capraro

Roy

Onuchic

et al. 2012

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

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“…6B, that the directly overlapping peptides between pro-and mature IL-1␤ are well protected and show similar or reduced solvent exchange protection over time. As the exchange protection along the ␤-strands and in the surface 90s loop hydrophobic mini-core has been (well documented by NMR studies of the mature protein) attributed to secondary structure interactions (anti-parallel ␤ strand hydrogen bonding), this is likely the cause for protection in pro-IL-1␤ as well (72). The pro-IL-1␤ native state heterogeneity appears likely due to the mobility of the N-terminal 116 residues as these residues have minimal stabilization to solvent exchange (Fig.…”

Section: Geometric Frustration During Folding Is Linked To Function Imentioning

confidence: 91%

Pro-interleukin (IL)-1β Shares a Core Region of Stability as Compared with Mature IL-1β While Maintaining a Distinctly Different Configurational Landscape

Hailey¹,

Andersen³

et al. 2009

Journal of Biological Chemistry

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Interleukin-1␤ (IL-1␤) is a master cytokine involved in initiating the innate immune response in vertebrates (Dinarello, C. A. (1994) FASEB J. 8, 1314 -1325). It is first synthesized as an inactive 269-residue precursor (pro-interleukin-1␤ or pro-IL-1␤). Pro-IL-1␤ requires processing by caspase-1 to generate the active, mature 153-residue cytokine. In this study, we combined hydrogen/deuterium exchange mass spectrometry, circular dichroism spectroscopy, and enzymatic digestion comparative studies to investigate the configurational landscape of pro-IL-1␤ and the role the N terminus plays in modulating the landscape. We find that the N terminus keeps pro-IL-1␤ in a protease-labile state while maintaining a core region of stability in the C-terminal region, the eventual mature protein. In mature IL-1␤, this highly protected region maps back to the area protected earliest in the NMR studies characterizing an on-route kinetic refolding intermediate. This protected region also encompasses two important functional loops that participate in the IL-1␤/receptor binding interface required for biological activity. We propose that the purpose of the N-terminal precursor region in pro-IL-1␤ is to suppress the function of the eventual mature region while keeping a structurally and also functionally important core region primed for the final folding into the native, active state of the mature protein. The presence of the self-inhibiting precursor region provides yet another layer of regulation in the life cycle of this important cytokine.Nearly all cell types respond to interleukin (IL)-1␤, 4 in a very sensitive manner, via binding to the interleukin-1 receptor type 1 (IL-1RI) (2). Although essential in the immune response, overproduction of IL-1␤ can lead to both acute (sepsis) as well as chronic (rheumatoid arthritis, atherosclerosis, obesity, and diabetes) disease states (3). Thus, the expression, activation, and secretion of this cytokine are tightly controlled (4). Although many cell types express IL-1␤, it is predominately produced and secreted by monocytes and macrophages (1). The protein is synthesized as a biologically inactive 269-residue precursor molecule, pro-interleukin-1␤ (pro-IL-1␤), and the 153-residue active mature IL-1␤ is generated from the C-terminal domain. Processing of the proprotein involves the recently discovered NALP-1 and NALP-3 inflammasomes, which are responsible for activating procaspase-1 (5). The inflammasome function is integral in wound repair as well as for combating infection (6 -9).In vivo, the 31-kDa pro-IL-1␤ precursor is processed to the active C-terminal 17-kDa form by the interleukin-1 converting enzyme, caspase-1 (10, 11). Caspase-1 is a cysteine protease that recognizes two cleavage sites in pro-IL-1␤, the Asp 27 2Gly 28 and Asp 116 2Ala 117 peptide bonds (Fig. 1A). These cleavage sites are conserved across mammals (12-14). The activation pathway is believed to proceed with cleavage first at Asp 27 2Gly 28 (site 1) followed by Asp 116 2Ala 117 (site 2). These processing events lead ...

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“…As a result, it has become quite common to have structures of homologous proteins or even identical proteins solved simultaneously by separate research groups. For example, the structure of IL-lfl has recently been determined independently in three different laboratories as well as by an NMR method (Priestle, Schar & Grfitter, 1989;Finzel et al, 1989;Veerapandian et al, 1992;Clore, Wingfield & Gronenborn, 1991;Shaanan et al, 1992) and the structure of a cupredoxin has been solved independently in two laboratories (Adman et al, 1989;Petratos, Banner, Beppu, Wilson & Tsernoglou, 1987). While the comparison between homologous protein structures often provides insight into the functional mechanism of a protein, the comparison between identical structures measures the correctness and accuracy of the structure determinations.…”

Section: Introductionmentioning

confidence: 99%

Comparison of two crystal structures of TGF-β2: the accuracy of refined protein structures

Davies¹,

Schlunegger²,

Grütter³

1994

Acta Crystallogr D Biol Crystallogr

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Transforming growth factor-fl is a multifunctional cell-growth regulator and is a member of the TGF-fl superfamily of cytokines. Each monomer is 112 amino acids long and the mature active form is a 25 kDa homodimer. Recently, the crystal structure of TGF-fl2 has been determined independently in two laboratories [Daopin, Piez, Ogawa & Davies (1992). Science, 257, 369-373; Schlunegger & Grfitter (1992). Nature (London), 358,[430][431][432][433][434] and subsequently refined to higher resolutions [Daopin, Li & Davies (1993). Proteins Struct. Funct. Genet. In the press; Schlunegger & Griitter (1993). J. Mol. Biol. In the press]. A detailed structural comparison shows that the two structures are nearly identical with the differences mostly located on the mobile regions of the molecule. The r.m.s, differences between the two structures are 0.10 A for 104 pairs of C a atoms, 0.15 A for 434 pairs of main-chain atoms, 0.33 A for 860 out of 890 pairs of protein atoms and a correlation of 90% between the temperature B factors of all protein atoms. Based on a comparison of the water molecules, a B value of 60.0 A 2 is recommended as the cut off for modeling new waters. The structural identity is striking because in one case the material was expressed in vivo in CHO cells whereas in the other case it was expressed in E. coli and had to be refolded in vitro. The overall coordinate errors are estimated to be 0.21/~ from the Luzzati plot, 0.18 A from the O' A plot, 0.24 A with Cruickshank's equations and 0.25 A using the empirical method of Perry & Stroud. These estimates are comparable to the r.m.s, structure superposition. The r.m.s. differences correlate very well with the crystallographic B values and the relation is best described with the Cruickshank formula. In addition to the estimation of an overall error, a new application of the Cruickshank formula is presented here to estimate the local errors.

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Functional implications of interleukin‐1β based on the three‐dimensional structure

Cited by 79 publications

References 48 publications

β-Bulge triggers route-switching on the functional landscape of interleukin-1β

β-Bulge triggers route-switching on the functional landscape of interleukin-1β

Pro-interleukin (IL)-1β Shares a Core Region of Stability as Compared with Mature IL-1β While Maintaining a Distinctly Different Configurational Landscape

Comparison of two crystal structures of TGF-β2: the accuracy of refined protein structures

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