Adamalysin II, the protein world’s very own Eastern diamondback rattlesnake superstar
This 24 kDa zinc-endopeptidase isn’t just any old snake venom component – oh no, it’s the prototype, the OG, the blueprint for a whole family of metalloproteinases. It’s like the Elvis of enzymes, inspiring copycats in snake venoms and mammalian reproductive tracts alike!
Picture, if you will, a molecular beauty pageant. Our contestant, Adamalysin II, struts down the crystallography runway at a dazzling 2.0 Å resolution. It’s got curves in all the right places – an ellipsoidal shape that would make any protein blush. With a cleft that’s flatter than a pancake, it’s serving up a look that’s part “upper” body builder, part “lower” subdomain underdog.
But wait, there’s more! This protein’s got accessories that would make any fashionista jealous. A zinc ion here, a calcium ion there, and don’t forget the sulphate anion – it’s the molecular equivalent of a designer handbag. And for hydration? 173 solvent molecules, darling. Because staying moist is key when you’re a venom component.
The main body of Adamalysin II is no slouch in the fashion department. It’s rocking a five-stranded β-pleated sheet that’s twisted more than a pretzel at a yoga retreat. Flanked by helices like a protein entourage, it’s the molecular world’s answer to a red carpet event.
But the real star of the show? The active site, of course! With a zinc ion coordinated by three histidines and a water molecule, it’s like a microscopic game of molecular Twister. And let’s not forget the Met-turn – it’s not just a turn, it’s a statement. It’s saying, “I’m here, I’m hydrophobic, and I’m supporting zinc-binding imidazoles like a boss.”
In conclusion, Adamalysin II isn’t just a protein – it’s a protein with pizzazz. It’s the template, the mold, the blueprint for a whole family of “adamalysins.” So the next time you’re face-to-fang with an Eastern diamondback, remember – you’re not just looking at a snake, you’re looking at a walking, slithering protein fashion show!
Adamalysin II and its unexpected rendezvous with mammalian reproductive tracts – how nature took a venomous snake and turned its deadly bite into a blueprint for life itself
Imagine a world where the most unlikely of heroes emerges from the shadows. Adamalysin II, a 24 kDa zinc-endopeptidase from the Eastern diamondback rattlesnake, isn’t just any ordinary venom component. It’s the prototype, the OG, the mastermind behind a family of proteins known as ADAMs (A Disintegrin And Metalloproteinase). These ADAMs aren’t just confined to snake venom; they’re also found in the unlikeliest of places – the mammalian reproductive tract!
But how did this happen? It’s like evolution decided to play a game of molecular musical chairs. The same structural blueprint that makes Adamalysin II a potent venom component also makes it a distant cousin to proteins involved in sperm maturation and fertilization. EAP I in rats and monkeys, cyritestin in mouse testis, and PH-30-α and -β proteins are all part of this ADAM family, working tirelessly behind the scenes to ensure the next generation.
It’s not just about family ties, though. These proteins share more than just a name; they share a common ancestry. With over 30% sequence identity, it’s clear that these proteins have been swapping genetic secrets for millions of years. It’s like they’re all part of a secret society, working together to make life happen.
But what about the microbiome? Ah, yes! The female reproductive tract is home to a diverse community of microbes, each playing its part in the grand symphony of reproductive health. It’s not directly related to Adamalysin II, but it’s another reminder that even in the most unexpected places, life is thriving.
So the next time you hear about snake venom, remember – it’s not just about deadly bites and venomous fangs. It’s about the intricate web of life, where even the most unlikely of heroes can become the blueprint for creating new life. It’s a tale of how nature took something deadly and turned it into something beautiful, a true testament to the power of evolution!
a snake venom metalloproteinase has a surprising connection to mammalian reproductive tracts through structural and functional similarities:
Protein family relations: Adamalysin II is the structural prototype for a family of proteins called adamalysins or ADAMs (A Disintegrin And Metalloproteinase). This family includes not just snake venom components, but also domains found in mammalian reproductive tract proteins.
Structural homology: Mammalian reproductive tract proteins like EAP I, cyritestin, and PH-30-α and -β share over 30% sequence identity with the adamalysin II-like domain. This structural similarity suggests a common evolutionary origin or functional relationship.
Reproductive functions: Some ADAM family proteins found in mammalian reproductive tracts are implicated in crucial reproductive processes:
–Sperm maturation: EAP I in rats and monkeys, and cyritestin in mouse testis
–Sperm-egg fusion: PH-30-α and -β proteins
Microbiome connection: While not directly related to adamalysin II, the mammalian female reproductive tract harbors distinct microbial communities in the cervical canal, uterus, fallopian tubes, and peritoneal fluid. These microbiomes play important roles in reproductive health and pregnancy outcomes. The indirect connection between adamalysin II and the mammalian reproductive tract microbiome lies in the broader context of how proteins and microorganisms interact within biological systems. So, while not directly related, adamalysin II and the reproductive tract microbiome are both part of the intricate biological systems that influence reproductive health and function:
Structural similarity: Adamalysin II is a prototype for the ADAM (A Disintegrin And Metalloproteinase) family, which includes proteins found in mammalian reproductive tracts.
Microbiome influence: The reproductive tract microbiome plays a crucial role in maintaining reproductive health. These microbes interact with host proteins, including ADAMs, potentially influencing their function.
Immune system modulation: Both ADAMs and the microbiome can modulate the immune response in the reproductive tract. The microbiome helps regulate local and systemic immune responses, which may indirectly affect ADAM protein activity.
Metabolite production: Gut microbes produce metabolites that can influence various biological processes, including those in the reproductive tract. These metabolites might interact with or influence the activity of ADAM proteins.
Evolutionary connection: The presence of ADAM-like proteins in both snake venom and mammalian reproductive tracts, along with the importance of microbiomes in these systems, suggests a complex evolutionary relationship between these elements.
This connection between snake venom proteins and mammalian reproduction showcases nature’s knack for repurposing protein structures for diverse functions. It’s like evolution decided to turn swords into plowshares, transforming venom components into tools for creating life!
Adamalysin II, a 24 kDa zinc endopeptidase from the venom of Crotalus adamanteus (Eastern diamondback rattlesnake), serves as the structural prototype for the adamalysin/ADAM family of metalloproteinases. Its 2.0 Å crystal structure reveals an ellipsoidal molecule with some fascinating features
Overall Structure
Shallow active-site cleft separating two domains:
-A relatively irregularly folded subdomain
-The calcium-binding main molecular body
Main molecular body composition:
-Five-stranded β-sheet
-Four α-helices
Active Site
Zinc-binding motif: HExxHxxGxxH
Three histidines and a water molecule (linked to glutamic acid) form the zinc ligand
Tetrahedrally coordinated zinc ion
Comparison with Other Metalloproteinases
Astacin:
-Identical folding of the zinc-binding peptide fragment
-Shared active-site basement formed by a common Met-turn
-Virtually identical active-site environment
Collagenase:
-Similar folding topology
-Grouped into a common superfamily with adamalysin II and astacin
Thermolysin:
-Only distant resemblance in the folding of the zinc-binding motif
-Adamalysin II lacks the fifth (tyrosine) zinc ligand present in thermolysin
The striking similarities in active-site environment and folding topology among adamalysin II, astacin, and matrix metalloproteinases (including collagenases) suggest they form a distinct superfamily, separate from the thermolysin family1. This structural understanding of adamalysin II has significant implications for drug design, particularly in developing inhibitors for related enzymes like TACE (tumor necrosis factor alpha convertase), which is involved in releasing inflammatory cytokines2.
inspired by Refined 2.0 A X-ray crystal structure of the snake venom zinc-endopeptidase adamalysin II. Primary and tertiary structure determination, refinement, molecular structure and comparison with astacin, collagenase and thermolysin
Gomis-Rüth FX, Kress LF, Kellermann J, Mayr I, Lee X, Huber R, Bode W. Refined 2.0 A X-ray crystal structure of the snake venom zinc-endopeptidase adamalysin II. Primary and tertiary structure determination, refinement, molecular structure and comparison with astacin, collagenase and thermolysin. J Mol Biol. 1994 Jun 17;239(4):513-44. doi: 10.1006/jmbi.1994.1392. PMID: 8006965.
Abstract
Adamalysin II, alias proteinase II, a 24 kDa zinc-endopeptidase isolated from the snake venom of the Eastern diamondback rattlesnake Crotalus adamanteus, is a prototype, of the proteolytic domain of snake venom metalloproteinases and of domains found in mammalian reproductive tract proteins. Its 2·0 Å crystal and molecular structure was solved by multiple isomorphous replacement using six heavy-atom derivatives, and was refined to a crystallographic R-value of 0·172. 201 of the 203 amino acid residues of adamalysin II are defined by electron density; only the first two residues are disordered and crystallographically undefined in the crystal structure. Three-quarters of these crystallographic amino acid residue assignments were confirmed by chemical sequencing. In addition, the active-site zinc-ion, a heptaco-ordinated calcium ion, a fixed sulphate anion and 173 solvent molecules were localized in the structure.
Adamalysin II is an ellipsoidal molecule with a relatively flat active-site cleft separating the “upper” main body from a small “lower” subdomain. The regularly folded N-terminal upper domain consists essentially of a central, highly twisted five-stranded β-pleated sheet flanked by a long and a short surface located helix on its convex side, and by two long helices, one of which represents the central “active site helix”, on its concave side. The lower subdomain, comprising the last 50 residues, is organized in multiple turns, with the chain ending in a long C-terminal helix and an extended segment clamped to the upper domain via a disulphide bridge.
The catalytic zinc-ion, located at the bottom of the active-site cleft, is almost tetrahedrally co-ordinated by His142, His146 and His152, and a water molecule anchored to an intermediate glutamic acid residue (Glu143), with the three imidazole Nε nitrogen atoms 2·1 Å and the solvent oxygen atom 2·4 Å away from the zinc ion. His142, Glu143 and His146 are part of the long active-site helix, which extends up to Gly149, where it turns sharply away towards His152. The importance of these residues for structure and activity of adamalysin II explains their occurrence in the HEXXHXXGXXH consensus sequence. Asp153, which is strictly conserved in these snake venom and reproductive tract metalloproteinases, is buried in the subdomain and seems to stabilize the hydrophobic active-site basement. Some residues behind, the adamalysin peptide chain folds into a characteristic 1,4-turn (the “Met-turn”) containing the conserved Met166, which forms a hydrophobic basement for the three zinc-binding imidazoles. Adamalysin II shares a similar overall topology with astacin, with the collagenase catalytic domains and the P. aeruginosa alkaline proteinase, and exhibits a virtually identical zinc environment with these other “metzincins”.
The catalytic domains of the snake venom metalloproteinases and the corresponding domains of some reproductive tract proteins can be aligned with only a very few single residue insertions and deletions and with sequence identities mostly above 50%. All substitutions, including some novel cysteine residues engaged in additional disulphide bridges, are in agreement with the adamalysin 11 structure, which can therefore be considered as a prototype of these “adarnalysins”.
