Solution Structure of the Calponin Homology (CH) Domain from the Smoothelin-like 1 Protein

Ishida, Hiroaki; Borman, Meredith A.; Ostrander, Janina; Vogel, Hans J.; MacDonald, Justin A.

doi:10.1074/jbc.m800627200

Cited by 28 publications

(21 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both myosin light chain kinase and myosin phosphatase are regulated by several accessory proteins, and one such protein is smoothelin-like protein 1 (SMTNL1) (9). Mouse SMTNL1 is divided into two separate domains: a unique N-terminal domain (amino acids 1-346) and a C-terminal single, type-2 calponin homology domain (amino acids 346 -459) that is helix-rich and globular in structure essential for binding tropomysin (9,10). Physiological studies in smtnl1 Ϫ/Ϫ mice indicate that the protein plays a key role in modulating the contractile activity of smooth and striated muscle and is involved in adaptation in response to exercise and pregnancy (11,12).…”

Section: Smtnl1 Is a Bifunctional Co-regulator Of Pr-b Signaling And mentioning

confidence: 99%

Smoothelin-like 1 Protein Is a Bifunctional Regulator of the Progesterone Receptor during Pregnancy

Bodoor

Lontay

Safi

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

During pregnancy, uterine smooth muscle (USM) coordinately adapts its contractile phenotype in order to accommodate the developing fetus and then prepare for delivery. Herein we show that SMTNL1 plays a major role in pregnancy to promote adaptive responses in USM and that this process is specifically mediated through interactions of SMTNL1 with the steroid hormone receptor PR-B. In vitro and in vivo SMTNL1 selectively binds PR and not other steroid hormone receptors. The physiological relationship between the two proteins was also established in global gene expression and transcriptional reporter studies in pregnant smtnl1 ؊/؊ mice and by RNA interference in progesterone-sensitive cell lines. We show that the contraction-associated and progestin-sensitive genes (oxytocin receptor, connexin 43, and cyclooxygenase-2) and prolactins are down-regulated in pregnant smtnl1 ؊/؊ mice. We suggest that SMTNL1 is a bifunctional co-regulator of PR-B signaling and thus provides a molecular mechanism whereby PR-B is targeted to alter gene expression patterns within USM cells to coordinately promote alterations in USM function during pregnancy.Uterine smooth muscle (USM) 5 cells show a high degree of plasticity and are capable of transforming their phenotype in response to a variety of physiological stresses, such as pregnancy. In pregnancy, USM cells go through a number of extensive phenotypic changes characterized by the expression of a distinct set of proteins (1, 2). In early pregnancy, USM cells proliferate rapidly under the influence of endocrine-stimulated growth factors (3). A significant increase in the expression of anti-apoptotic factors is a key feature of this proliferative phase (4). In midpregnancy, USM cells switch into a synthetic phase characterized by cellular hypertrophy, extracellular matrix remodeling, and activation of apoptotic pathways (3). The changes that occur during this phase are under the influence of both mechanical stimuli and endocrine hormones, such as progesterone (2). Toward parturition, the cells adopt a more contractile phenotype, characterized by an up-regulation in the expression of contraction-associated proteins (CAPs) (2). The phenotypic changes in this phase are modulated by mechanical stimuli and sex-related hormones, such as progesterone and estrogen. The molecular mechanisms regulating the transition of the USM through these different stages are limited, and investigation of these mechanisms is of great importance given the fact that preterm labor is still the leading cause of neonatal morbidity and mortality (5, 6).USM contraction is mainly regulated by phosphorylation of the regulatory light chain of myosin (MLC20) by Ca 2ϩ /calmodulin-dependent myosin light chain kinase, whereas relaxation is promoted by dephosphorylation of MLC20 by myosin phosphatase (7,8). Both myosin light chain kinase and myosin phosphatase are regulated by several accessory proteins, and one such protein is smoothelin-like protein 1 (SMTNL1) (9). Mouse SMTNL1 is divided into two separate domains: a uniqu...

show abstract

Section: Smtnl1 Is a Bifunctional Co-regulator Of Pr-b Signaling And mentioning

confidence: 99%

Smoothelin-like 1 Protein Is a Bifunctional Regulator of the Progesterone Receptor during Pregnancy

Bodoor

Lontay

Safi

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…A potential protein effector of PP1M is smoothelin-like protein 1 (SMTNL1) (26 -28). SMTNL1 contains a calponin homology domain (CH2) at its C terminus while the remaining two-thirds of the primary sequence is entirely unique within the mammalian databases (26,29). Gene deletion studies in mice demonstrated that SMTNL1 plays a role in cGMP/cAMP-mediated adaptations to exercise involving direct modulation of contractile activity in vascular smooth muscle.…”

mentioning

confidence: 99%

Smoothelin-like 1 Protein Regulates Myosin Phosphatase-targeting Subunit 1 Expression during Sexual Development and Pregnancy*

Lontay

Bodoor

Weitzel

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Pregnancy coordinately alters the contractile properties of both vascular and uterine smooth muscles reducing systemic blood pressure and maintaining uterine relaxation. The precise molecular mechanisms underlying these pregnancy-induced adaptations have yet to be fully defined but are likely to involve changes in the expression of proteins regulating myosin phosphorylation. Here we show that smoothelin like protein 1 (SMTNL1) is a key factor governing sexual development and pregnancy induced adaptations in smooth and striated muscle. A primary target gene of SMTNL1 in these muscles is myosin phosphatase-targeting subunit 1 (MYPT1). Deletion of SMTNL1 increases expression of MYPT1 30 -40-fold in neonates and during development expression of both SMTNL1 and MYPT1 increases over 20-fold. Pregnancy also regulates SMTNL1 and MYPT1 expression, and deletion SMTNL1 greatly exaggerates expression of MYPT1 in vascular smooth muscle, producing a profound reduction in force development in response to phenylephrine as well as sensitizing the muscle to acetylcholine. We also show that MYPT1 is expressed in Type2a muscle fibers in mice and humans and its expression is regulated during pregnancy, suggesting unrecognized roles in mediating skeletal muscle plasticity in both species. Our findings define a new conserved pathway in which sexual development and pregnancy mediate smooth and striated muscle adaptations through SMTNL1 and MYPT1.

show abstract

“…It was expected that the phosphorylation of SMTNL1-TMB by PKA would impact the association with Ca-CaM and not with apo-CaM, since the binding of the latter was linked to an IQ-domain at the C-terminus (CBD2, amino acids 439–457 [10]). Indeed, we observed reductions in Ca-CaM-Sepharose binding for phosphorylated SMTNL1-TMB, with recovery of approximately 30% less bound material (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…CaM provides signaling by association with specific binding sites in target proteins, both in its calcium-saturated (Ca-CaM) or its calcium-free (apo-CaM) form [8, 9]. We have previously reported that SMTNL1 possesses two CaM-binding sites: a classic CaM-binding domain (CBD1, amino acids 310–325) in the center of the protein as well as an IQ-motif that serves as an apo-CaM-binding site (CDB2, amino acids 439–457) located in the carboxy-terminal calponin homology domain [10–12]. SMTNL1 was established as a bona fide CaM-binding protein within aortic A7r5 smooth muscle cells using the proximity ligation assay.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Binding of smoothelin-like 1 to tropomyosin and calmodulin is mutually exclusive and regulated by phosphorylation

et al. 2017

Self Cite

View full text Add to dashboard Cite

BackgroundThe smoothelin-like 1 protein (SMTNL1) can associate with tropomyosin (Tpm) and calmodulin (CaM), two proteins essential to the smooth muscle contractile process. SMTNL1 is phosphorylated at Ser301 by protein kinase A during calcium desensitization in smooth muscle, yet the effect of SMTNL1 phosphorylation on Tpm- and CaM-binding has yet to be investigated.ResultsUsing pull down studies with Tpm-Sepharose and CaM-Sepharose, we examined the interplay between Tpm binding, CaM binding, phosphorylation of SMTNL1 and calcium concentration. Phosphorylation greatly enhanced the ability of SMTNL1 to associate with Tpm in vitro; surface plasmon resonance yielded a 10-fold enhancement in K D value with phosphorylation. The effect on CaM binding is more complex and varies with the availability of calcium.ConclusionsCombining both CaM and Tpm with SMTNL1 shows that the binding to both is mutually exclusive.Electronic supplementary materialThe online version of this article (doi:10.1186/s12858-017-0080-6) contains supplementary material, which is available to authorized users.

show abstract

Solution Structure of the Calponin Homology (CH) Domain from the Smoothelin-like 1 Protein

Cited by 28 publications

References 57 publications

Smoothelin-like 1 Protein Is a Bifunctional Regulator of the Progesterone Receptor during Pregnancy

Smoothelin-like 1 Protein Is a Bifunctional Regulator of the Progesterone Receptor during Pregnancy

Smoothelin-like 1 Protein Regulates Myosin Phosphatase-targeting Subunit 1 Expression during Sexual Development and Pregnancy*

Binding of smoothelin-like 1 to tropomyosin and calmodulin is mutually exclusive and regulated by phosphorylation

Contact Info

Product

Resources

About