BSK1-2 aging-research peptide fragment
A short piece of the GDF-11 protein, taken from the region that normally keeps it in check; used in lab studies of aging and tissue biology, research tool only, not an approved drug.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
The GDF-11 propeptide LAP fragment is a 16-amino-acid segment derived from the junction between the prodomain and the mature growth factor domain of GDF-11 (Growth Differentiation Factor 11), a secreted protein belonging to the TGF-β superfamily. The sequence RRKRSPPDPICPHHPE spans the furin protease recognition motif (RRKR) and the opening residues of the mature GDF-11 domain — meaning it sits at the precise point where the precursor protein is first cut to generate the active signaling molecule. GDF-11 itself is best known as a circulating factor whose levels and tissue effects have been hotly debated in aging research since 2013; this fragment captures the critical cleavage-site chemistry that controls when and whether the full-length protein becomes active.
The cysteine residue (C) within the mature-domain portion of this sequence participates in the disulfide-bond network of the active GDF-11 homodimer; the raw 16-letter sequence does not represent that redox chemistry.
History
GDF-11 was identified in 1999 by McPherron, Lawler, and Lee, who showed that mice lacking the gene developed anteriorly directed homeotic transformations throughout the axial skeleton, establishing GDF-11 as a secreted morphogen that specifies anterior–posterior positional identity during embryogenesis (McPherron and colleagues, Nature Genetics 1999). Interest in the prodomain biology developed in parallel with the discovery that GDF-11 and its close paralog myostatin (GDF-8) remain tightly bound to their cleaved prodomains after furin processing, forming latent complexes that cannot engage receptors until a second proteolytic step releases the active ligand (Ge and colleagues, Molecular and Cellular Biology 2005).
The field exploded in 2013 when Loffredo and colleagues reported, in heterochronic parabiosis experiments, that restoring circulating GDF-11 to youthful levels reversed age-related cardiac hypertrophy in old mice (Loffredo and colleagues, Cell 2013). Subsequent work complicated this picture: antibody cross-reactivity with the highly homologous myostatin meant many early measurements did not distinguish the two proteins, and mass-spectrometry-based assays later showed it was GDF-8, not GDF-11, that predominantly declines with age in circulation (Ben Driss and colleagues, Journal of Cardiovascular Aging 2023). The propeptide's role as a natural inhibitor and solubility scaffold for the mature domain was characterized in detail by Pepinsky and colleagues at Biogen (Biochemistry 2017).
What it does
This 16-residue fragment sits at the functional boundary of GDF-11 activation. The N-terminal half (RRKR) is the recognition sequence for furin-like proprotein convertases, which cleave the precursor protein at this site inside the cell. After cleavage, the prodomain does not simply dissociate — it stays noncovalently wrapped around the mature domain, holding it in an inactive latent complex that cannot bind cell-surface receptors. A second protease family (Tolloid metalloproteinases, including BMP1 and mTLL1) must then cleave within the prodomain to release the active GDF-11 ligand into the extracellular space.
The broader prodomain, including residues 43–115, is necessary and sufficient for this latency function (Walker and colleagues, Circulation Research 2016). A 6-kDa prodomain fragment spanning approximately residues 60–114 (which overlaps the mature domain junction represented in this card's sequence) has been found to remain associated with mature GDF-11 after proteolytic activation in biochemical reconstitution experiments; that fragment does not inhibit GDF-11 signaling activity but does dramatically improve the solubility of the mature domain at neutral pH, acting as a natural chaperone (Pepinsky and colleagues, Biochemistry 2017). The specific activity of the GDF-11/PDP60–114 complex was reported as equivalent to mature GDF-11 alone (EC50 approximately 1 nM in that study).
Once fully activated, GDF-11 signals by binding to activin type II receptors (ActRIIA and ActRIIB), which recruit type I receptors (ALK4 and ALK5) and trigger phosphorylation of SMAD2 and SMAD3. Those phosphorylated SMADs translocate to the nucleus and regulate gene expression programs that govern cell differentiation, tissue homeostasis, and organismal aging (Walker and colleagues, Circulation Research 2016; Ma and colleagues, Aging 2021).
Evidence
- Human: Heterozygous loss-of-function variants in the GDF11 gene cause a multi-system developmental syndrome in humans, with features including craniofacial abnormalities (cleft palate, lip), vertebral hypersegmentation, neurological deficits, cardiac and auditory findings — establishing that precise regulation of GDF-11 dosage is required for normal human development (Ravenscroft and colleagues, Genetics in Medicine 2021). No clinical trials of this specific 16-aa fragment have been registered.
- Animal: The GDF-11 propeptide fused to an Fc domain (GDF11PRO-Fc) functions as a dual inhibitor of GDF-11 and myostatin, increasing limb muscle mass by 17–26% and improving grip strength by 28–36% in mdx dystrophic mice following systemic AAV9 delivery (Jin and colleagues, Skeletal Muscle 2019). Ge and colleagues demonstrated that prodomain-resistant (BMP1-cleavage-blocked) GDF-11 mutants modulate NGF-induced differentiation of PC12 neuronal cells, showing that tolloid-controlled prodomain release governs GDF-11 bioavailability in neural contexts (Molecular and Cellular Biology 2005).
- In vitro: The isolated prodomain fragment PDP60–114 (overlapping this card's sequence at its C-terminus) maintains mature GDF-11 in a soluble, fully active state with EC50 approximately 1 nM in SMAD2/3 reporter assays; the full-length prodomain by contrast is a potent antagonist (Pepinsky and colleagues, Biochemistry 2017).
Known effects
- Furin cleavage gating — The RRKR motif is cleaved by proprotein convertases (furin, PCSK5) as a prerequisite for GDF-11 maturation; Preclinical/biochemical
- Latent complex formation — The prodomain sequence adjacent to RRKR mediates noncovalent sequestration of the mature GDF-11 domain, holding it in a receptor-inaccessible state; Mechanistic
- Solubility enhancement — The C-terminal prodomain fragment (including residues around the cleavage junction) prevents aggregation of mature GDF-11 at physiological pH without inhibiting activity; In vitro
- GDF-11/myostatin dual inhibition (propeptide-Fc context) — When used as a therapeutic fusion protein, the propeptide region blocks both GDF-11 and myostatin but not activin A, selectively attenuating ActRII signaling; Preclinical (mdx mice)
Safety signals
No safety data specific to this 16-aa fragment has been published. In propeptide-Fc fusion studies in mdx mice, GDF11PRO-Fc increased muscle mass without reducing dystrophic histopathology markers (fibrosis, membrane permeability, serum CK), suggesting muscle-mass effects can be dissociated from disease-modifying effects (Jin and colleagues, Skeletal Muscle 2019). Supraphysiological doses of active GDF-11 itself produce cachexia and death in mice, underscoring that tight control of GDF-11 bioavailability — which this fragment participates in — is biologically essential (Ben Driss and colleagues, Journal of Cardiovascular Aging 2023).
Regulatory status
- US / EU: No regulatory filings. This is a research peptide fragment, not an approved or investigational drug.
- ClinicalTrials.gov: No registered trials for this specific fragment. GDF-11 pathway modulation more broadly has not yet entered registered human trials as of June 2026.
Mechanism
GDF-11 is synthesized as a 407-aa prepropeptide. After removal of the signal peptide, the prodomain (roughly aa 25–298) and mature domain (aa 299–407) are connected by the RRKR furin recognition motif. Proprotein convertases cleave at RRKR, but the resulting prodomain–mature domain complex remains noncovalently associated — a latent, receptor-inaccessible state analogous to the TGF-β LAP complex. The prodomain "latency lasso" wraps around the fingertip region of the mature domain, physically occluding both the type I and type II receptor binding sites (Walker and colleagues, Circulation Research 2016).
Extracellular Tolloid metalloproteinases (BMP1, mTLL1, mTLL2) cleave the prodomain at Gly119–Asp120; the Asp120 residue is critical — alanine substitution abolishes BMP1-mediated cleavage entirely (Ge and colleagues, Molecular and Cellular Biology 2005). Tolloid cleavage destabilizes the latent complex, enabling the mature GDF-11 homodimer to engage ActRIIA or ActRIIB on the cell surface. Receptor occupation triggers ActRII-mediated phosphorylation of the GS domain of the type I receptor (ALK4 or ALK5), which then phosphorylates SMAD2 and SMAD3. Phospho-SMAD2/3 complexes with SMAD4 and translocate to the nucleus to regulate target gene expression. Non-canonical signaling through MAP3K7/TAK1, p38 MAPK, and ERK also participates in some cell types (Jamaiyar and colleagues, Pharmacology & Therapeutics 2017).
This card's 16-aa fragment, RRKRSPPDPICPHHPE, straddles the furin cut site: the four N-terminal residues (RRKR) are consumed by furin recognition, while the remaining twelve residues (SPPDPICPHHPE) are the opening sequence of the mature domain. The cysteine at position 11 of the fragment (the C in …PIC…) is part of the cystine-knot structure of the mature GDF-11 homodimer and is involved in inter-chain disulfide bonding; this chemistry is absent from the raw single-letter sequence.
Open questions
- The precise contribution of the short C-terminal prodomain fragment (residues 60–114, which includes this card's mature-domain-side residues) to in vivo GDF-11 bioavailability has only been studied in vitro; whether this fragment circulates associated with active GDF-11 in blood is not established.
- Whether RRKR-spanning fragments derived from proteolytic turnover of the GDF-11 precursor have any independent receptor-binding or signaling activity remains uncharacterized.
- The selectivity profile of the propeptide region across other TGF-β superfamily members beyond GDF-11 and myostatin has not been systematically mapped.
- No head-to-head comparison of prodomain-derived inhibitors vs. antibody-based GDF-11/myostatin neutralization exists in an aging or muscle-wasting context.
Related peptides
- GDF-11 (mature domain) — the active signaling ligand released from this precursor after furin and Tolloid processing; signals via ActRIIA/B and SMAD2/3.
- Myostatin (GDF-8) — the closest paralog (89% mature-domain identity, 52% prodomain identity); shares the latent-complex activation mechanism and is co-inhibited by propeptide-Fc constructs derived from either protein.
- See also: GDF-11 signaling context is shared with other TGF-β/activin family members that use the same SMAD2/3 nuclear pathway.
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
Could this small peptide slow down the molecular scissors that turn the GDF-11 protein on?
If true, it could offer a way to fine-tune a key aging-linked protein without expensive antibody drugs. This might matter for conditions where GDF-11 activity is harmful, such as certain muscle-wasting or fibrosis settings.
Do small differences in the amino acids surrounding the cleavage site allow this peptide to tell GDF-11 apart from myostatin?
If true, it could allow researchers to study or therapeutically manipulate GDF-11 without accidentally altering muscle-mass regulation controlled by myostatin, which would reduce side effects in any future drug development.
If the single cysteine in this peptide were replaced with a more stable building block, would it remain active but survive in the bloodstream?
If true, this one change could transform a fragile research peptide into a candidate for animal studies, substantially shortening the path to a potential aging-related therapy.
Could blocking the activation of GDF-11 in aged muscle help satellite cells, the cells that repair muscle, do their job better?
If true, this could point toward a treatment for the muscle loss that comes with aging, helping older adults stay stronger and recover better from injury or illness.
Do the three proline amino acids in the middle of this peptide hold it straight so both ends can grab different proteins at the same time?
If true, the peptide could act on two biological pathways with a single molecule. That could mean stronger effects at lower doses, relevant to therapies that need to control GDF-11 in aging or regenerative medicine.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.17384468019008636 | boltz-2 |
| ranking score | 0.29421815276145935 | boltz-2 |
▸3-letter notation
▸recipeboltz-2 2.2.1
| parameter | value |
|---|---|
| model | boltz-2 2.2.1 |
| weights | — |
| hardware | vast_v100_32gb |
| mlx version | — |
| python | — |
| random seed | 1 |
| msa strategy | colabfold_local |
| runtime | — |
| predicted by | — |
| predicted at | 2026-05-23 |
▸citationbibtex
@peptide{pep10794,
sequence = {RRKRSPPDPICPHHPE},
target = {gdf-11},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}